CN110452158A

CN110452158A - The synthetic method of halofuginone hydrobromide and its intermediate with optical activation

Info

Publication number: CN110452158A
Application number: CN201910090473.8A
Authority: CN
Inventors: 金冶华; 邱发洋; 徐华; 尹文浩
Original assignee: Guangzhou Langqi Pharmaceutical Science And Technology Co Ltd
Current assignee: Guangzhou Langqi Biotechnology Co ltd
Priority date: 2019-01-30
Filing date: 2019-01-30
Publication date: 2019-11-15
Anticipated expiration: 2039-01-30
Also published as: CN110452158B

Abstract

The present invention relates to a kind of preparation method of cis- -2- (2- Chloroallyl) -3- hydroxy piperidine with optical activation and its preparing the application in halofuginone hydrobromide.The preparation method of cis- -2- (2- Chloroallyl) -3- hydroxy piperidine with optical activation includes the following steps: (1) in the first organic solvent, cis- -2- (2- the Chloroallyl) -3- hydroxy piperidine and dibenzoyl tartaric acid or derivatives thereof of racemization are subjected to salt-forming reaction and generate precipitating, the precipitating is recrystallized, chiral double salt is obtained；(2) in a second organic solvent, the chiral double salt is neutralized to alkalinity with alkaline aqueous solution, obtains cis- -2- with optical activation (2- Chloroallyl) -3- hydroxy piperidine.This method raw material is cheap and easy to get, preparation process is simple, impurity in products is few, is not necessarily to column chromatographic purifying, and can realize the large-scale production and preparation of high-optical-purity halofuginone hydrobromide.

Description

The synthetic method of halofuginone hydrobromide and its intermediate with optical activation

Technical field

The present invention relates to chemosynthesis technical fields, more particularly to a kind of halofuginone hydrobromide with optical activation and among it The synthetic method of body.

Background technique

The Changshan Alkaloid isolated from Chinese medicine Changshan includes orixine (Febrifugine), isofebrifugine (Isofebrifugine) and its halide derivative halofuginone hydrobromide (Halofuginone) has a variety of pharmacological activity, especially closely Year over to halofuginone hydrobromide more and more researches show that, the prevention and treatment in addition to being used as animal's coccidiosis etc., halofuginone hydrobromide exists Also there are a variety of important pharmacological actions in terms of human body diseases.Halofuginone hydrobromide specificity inhibits fibroblast synthesis type i collagen fine Dimension, to prevent the disease characterized by type i collagen synthesis excessively such as liver fibrosis, pulmonary fibrosis, chorionitis.Collage synthesis is pressed down System causes effects of tumors growth that there is the cell activity of key effect to reduce and then influences angiogenic growth and cell proliferation, blocks swollen Tumor cell growth and transfer, therefore halofuginone hydrobromide entered the clinic of FDA approval for treating the research of malignant tumour in 2000 Experimental stage.

Orixine is the natural products isolated from Changshan, and absolute configuration 2R, 3S, optically-active is "+", i.e. dextrorotation optics Activity；And its derivative halofuginone hydrobromide is without optically active raceme used in the veterinary drug.In recent years to the numerous of halofuginone hydrobromide Show that the pharmacological activity of dextrorotation -2R, the 3S- halofuginone hydrobromide of absolute configuration identical as natural products orixine is substantially better than in research Left-handed -2S, 3R- halofuginone hydrobromide.Therefore, there is the halofuginone hydrobromide of high optical activity to have a very important significance for synthesis.

The piperidine ring segment of halofuginone hydrobromide and Changshan Alkaloid contains into the trans- position 2- and the chiral centre of the position 3- two, In Mainly include following several method in the Chiral Synthesis of report: (1) passing through Sharpless asymmetric dihydroxylation Or Sharpless epoxidation constructs 2- and 3- chiral centres；(2) 3- chiral centre hydroxyls are introduced by yeast reducing carbonyl Base；(3) 3- chiral hydroxyl groups are introduced by acetylase；(4) the asymmetric aldol condensation of chiral small molecule compound catalysis is anti- It is chiral that 3- hydroxyls should be constructed；(5) chemical resolution is carried out by strychnia etc.；(6) using chipal compounds as starting material Synthetic method etc..The method of these related asymmetric syntheses optical activity halofuginone hydrobromides or orixine, it is numerous that there are synthetic routes The disadvantages of trivial, severe reaction conditions, yield are low, it is complicated to isolate and purify or use severe toxicity, expensive reagent.

Summary of the invention

Based on this, the present invention provides a kind of cis- -2- (2- Chloroallyl) -3- hydroxy piperidines with optical activation Preparation method, this method simple process, impurity in products be few, is not necessarily to column chromatographic purifying, be applied to prepare it is optically active normal , it can be achieved that the large-scale production and preparation of high-optical-purity halofuginone hydrobromide in the ketone of mountain.

Specific technical solution is as follows:

A kind of preparation method of cis- -2- (2- Chloroallyl) -3- hydroxy piperidine with optical activation, including walk as follows It is rapid:

(1) in the first organic solvent, by cis- -2- (2- the Chloroallyl) -3- hydroxy piperidine and dibenzoyl of racemization Tartaric acid or derivatives thereof carries out salt-forming reaction and generates precipitating, and the precipitating is recrystallized, chiral double salt is obtained；

(2) in a second organic solvent, the chiral double salt is neutralized to alkalinity with alkaline aqueous solution, obtained with optics Active cis- -2- (2- Chloroallyl) -3- hydroxy piperidine；

Cis- -2- (2- the Chloroallyl) -3- hydroxy piperidine of the racemization has structure shown in formula (±) -9；It is described to have Optically active cis- -2- (2- Chloroallyl) -3- hydroxy piperidine has structure shown in formula (+) -9 or formula (-) -9；Described two Benzoyltartaric acid or derivatives thereof has structure shown in formula 15 or formula 16；The chirality double salt has 17 institute of formula 14 or formula Show structure；Reaction equation is as follows:

Alternatively,

Wherein, each R is separately selected from: hydrogen or C₁-C₄Alkoxy.

In wherein some embodiments, the dibenzoyl tartaric acid or derivatives thereof of formula 15 described in step (1) is L- (-)-dibenzoyl tartaric acid or L- (-)-di-p-methoxy benzoyltartaric acid, the dibenzoyl tartaric acid of formula 16 or its derivative Object is D- (+)-dibenzoyl tartaric acid or D- (+)-di-p-methoxy benzoyltartaric acid.

In wherein some embodiments, cis- -2- (2- Chloroallyl) -3- hydroxyl piperazine of racemization described in step (1) The molar ratio of pyridine and dibenzoyl tartaric acid or derivatives thereof is 1:1~2.

In wherein some embodiments, the recrystallization is in the third organic solvent and water that volume ratio is 1~10:1 In the mixed solvent carries out；The third organic solvent is in ethyl alcohol, methanol, isopropanol, acetonitrile, Isosorbide-5-Nitrae-dioxane and acetone Any one or more.

In wherein some embodiments, the recrystallization is in the mixed of the third organic solvent and water that volume ratio is 3~5:1 It is carried out in bonding solvent；The third organic solvent is acetonitrile.

In wherein some embodiments, the first organic solvent described in step (1) is selected from ethyl alcohol, methanol, isopropanol, second Nitrile, methylene chloride, Isosorbide-5-Nitrae-dioxane, tetrahydrofuran, toluene, acetone, any one or more in ethyl acetate；And/or Any one or more of second organic solvent in ethyl acetate, methylene chloride and chloroform described in step (2).

In wherein some embodiments, the temperature of the salt-forming reaction is 0~100 DEG C；And/or the temperature of the recrystallization Degree is 0~30 DEG C.

In wherein some embodiments, the temperature of the salt-forming reaction is 20~40 DEG C；And/or the temperature of the recrystallization Degree is 15~28 DEG C.

In wherein some embodiments, alkaline aqueous solution described in step (2) is sodium hydrate aqueous solution, potassium hydroxide Any one in aqueous solution, lithium hydroxide aqueous solution, wet chemical and aqueous sodium carbonate, the alkalinity that is neutralized to is Being neutralized to pH is 8~14.

In wherein some embodiments, the synthetic method of cis- -2- (2- Chloroallyl) -3- hydroxy piperidine of the racemization Include the following steps:

(a) it is anti-with 2,3- dichloropropylene alkylation to occur for acetamino diethyl malonate under alkali and catalyst action It answers, the compound of production 2；

(b) compound of formula 2 issues raw hydrolysis decarboxylation reaction, the compound of production 3 in acid catalysis；

(c) esterification, the compound of production 4 occur under acid catalysis for the compound of formula 3；

(d) alkylated reaction of nitrogen occurs under the action of alkali and catalyst with the halogenated butyrate of 4- for the compound of formula 4, so The protection for carrying out nitrogen with amido protecting agent again afterwards is reacted, the compound of production 5；

(e) under alkali effect Dieckmann condensation reaction, the compound of production 6 occur for the compound of formula 5；

(f) compound of formula 6 issues raw decarboxylic reaction, the compound of production 7 in inorganic salt action；

(g) compound of formula 7 is acted on through reducing agent occurs reduction reaction, the compound of production 8；

(h) deprotection reaction of nitrogen, the compound of production 9 occur for the compound of formula 8；

Reaction equation is as follows:

Wherein:

R₁It is selected from: methyl, ethyl, n-propyl, isopropyl or tert-butyl, preferably methyl and ethyl；

R₂It is selected from: methyl, ethyl；

R₃Be selected from: methoxycarbonyl base, ethoxycarbonyl, tertiary fourth oxygen formoxyl, carbobenzoxy base, tri-chloroethoxy formoxyl or Benzyl, preferably carbobenzoxy base.

In wherein some embodiments, step (a) alkali is selected from potassium carbonate, cesium carbonate, sodium carbonate, sodium hydroxide, hydrogen Lithia, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, lithium hydride, in hydrofining at least It is a kind of.

In wherein some embodiments, step (a) catalyst is the combination of quaternary ammonium salt and iodide, the quaternary ammonium salt Any one in tetrabutylammonium bromide, tetraethylammonium bromide, tetrabutylammonium iodide, benzyltriethylammoinium chloride, it is described Any one of iodide in sodium iodide, potassium iodide, lithium iodide.

In wherein some embodiments, the molar ratio of the quaternary ammonium salt and iodide is 1: 2~6.

In wherein some embodiments, the solvent of step (a) alkylated reaction is selected from acetonitrile, methanol, ethyl alcohol, N, N- Dimethyl acetamide, n,N-Dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, toluene, methylene chloride, Any one in 1,2- dichloroethanes.

In wherein some embodiments, the reaction temperature of step (a) alkylated reaction is 20~120 DEG C.

In wherein some embodiments, step (a) acetamino diethyl malonate, 2,3- dichloropropylene, catalysis The molar ratio of agent and alkali is 1: 1~2: 0.1~0.5: 1~3.

In wherein some embodiments, step (b) acid is hydrochloride aqueous solution, the concentration of the hydrochloride aqueous solution It is 5~12mol/L.

In wherein some embodiments, the compound of the formula 2 and the molar ratio of hydrogen chloride are 1: 5~30.

In wherein some embodiments, step (c) acid is any in sulfuric acid, phosphoric acid, hydrochloric acid, p-methyl benzenesulfonic acid It is a kind of.

In wherein some embodiments, the solvent of step (c) esterification is selected from ethyl alcohol, diethyl carbonate, carbonic acid At least one of dimethyl ester, methanol, propyl alcohol, benzylalcohol.

In wherein some embodiments, the reaction temperature of step (c) esterification is 0~120 DEG C.

In wherein some embodiments, step (d) alkali is selected from potassium carbonate, saleratus, cesium carbonate, sodium carbonate, carbon Sour hydrogen sodium, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, diisopropyl ethyl amine, 1,8- diazabicyclo [5.4.0] Any one in 11 carbon -7- alkene.

In wherein some embodiments, the halogenated butyrate of 4- described in step (d) is selected from 4- bromobutanoate, 4- chloro-butyric acid Any one in ester, 4- iodine butyrate.

In wherein some embodiments, catalyst described in step (d) is the combination of quaternary ammonium salt or quaternary ammonium salt and iodide, The quaternary ammonium salt is any in tetrabutylammonium bromide, tetraethylammonium bromide, tetrabutylammonium iodide, benzyltriethylammoinium chloride One kind, any one of the iodide in sodium iodide, potassium iodide.

In wherein some embodiments, the solvent of the alkylated reaction of step (d) nitrogen is acetonitrile, methanol, ethyl alcohol, N, N- dimethyl acetamide, n,N-Dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, toluene, dichloromethane Any one in alkane, 1,2- dichloroethanes.

In wherein some embodiments, the reaction temperature of the alkylated reaction of nitrogen described in step (d) is 20~100 DEG C.

In wherein some embodiments, the halogenated butyrate of compound Yu 4- of formula 4 described in step (d), alkali, catalyst Molar ratio is 1: 1~1.5: 1~3: 0.01~0.2.

In wherein some embodiments, amido protecting agent described in step (d) is selected from benzyl chloroformate, two dimethyl dicarbonates Butyl ester, methylchloroformate, ethyl chloroformate, trichloroethyl chloroformate, cylite, any one in benzyl chloride.

In wherein some embodiments, the molar ratio of amido protecting agent described in step (d) and the compound of formula 4 is 0.8~2:1.

In wherein some embodiments, the reaction temperature of the protection reaction of step (d) nitrogen is 0~100 DEG C.

In wherein some embodiments, the halogenated butyrate of 4- described in step (d) is 4- bromobutyrate.

In wherein some embodiments, amido protecting agent described in step (d) is benzyl chloroformate, the chloro-carbonic acid The molar ratio of the compound of benzyl ester and formula 4 is 0.8~1.2: 1, and the reaction temperature of the protection reaction of the nitrogen is 0~50 DEG C.

In wherein some embodiments, step (e) alkali be selected from sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, Sodium hydride, lithium hydride, lithium diisopropylamine, bis- (trimethyl silicon substrate) Sodamides, bis- (trimethyl silicon substrate) lithium amides, bis- (three Methylsilyl) any one in potassamide.

In wherein some embodiments, the solvent of step (e) the Dieckmann condensation reaction is selected from tetrahydrofuran, first The combination of benzene, dimethylbenzene, methyl tertiary butyl ether(MTBE), methanol, any one or two kinds in ethyl alcohol.

In wherein some embodiments, the molar ratio of the compound of the alkali and formula 5 of step (e) reaction is 1~3: 1.

In wherein some embodiments, the reaction temperature of Dieckmann condensation reaction described in step (e) is -20~80 ℃。

In wherein some embodiments, inorganic salts described in step (f) are selected from sodium chloride, lithium chloride, sodium bromide, lithium bromide In any one.

In wherein some embodiments, the molar ratio of the compound of step (f) inorganic salts and formula 6 is 1~3: 1.

In wherein some embodiments, the reaction dissolvent of step (f) decarboxylic reaction is the combination of organic solvent and water, The organic solvent is selected from dimethyl sulfoxide, sulfolane, N-Methyl pyrrolidone, DMAC N,N' dimethyl acetamide, N, N- dimethyl Any one in formamide.

In wherein some embodiments, the volume mass ratio of the compound of organic solvent, water and formula 6 in step (f) is 3 ~5: 0.1~1: 1.

In wherein some embodiments, the reaction temperature of decarboxylic reaction described in step (f) is 100~150 DEG C.

In wherein some embodiments, step (f) inorganic salts are lithium chlorides, and the reaction dissolvent of the decarboxylic reaction is The combination of N,N-dimethylformamide and water.

In wherein some embodiments, reducing agent described in step (g) be selected from sodium borohydride, potassium borohydride, lithium borohydride, It is bis- (2- methoxyethoxy) sodium aluminates of lithium aluminium hydride, dihydro, borine, sodium amalgam, any one in three tertiary butyoxy aluminium lithiums Kind.It is preferred that sodium borohydride.

In wherein some embodiments, the solvent of step (g) reduction reaction is ethyl alcohol.

In wherein some embodiments, the molar ratio 1~2: 1 of the compound of step (g) reducing agent and formula 7.

In wherein some embodiments, the temperature of step (g) reduction reaction is 0~10 DEG C.

In wherein some embodiments, R₃For carbobenzoxy base, the remove-insurance of nitrogen occurs under the action of an acid for the compound of formula 8 Shield reaction, the compound of production 9, the acid are selected from least one of hydrochloric acid, hydrobromic acid, sulfuric acid；It is taken off described in step (h) The solvent of protection reaction is the combination of acetic acid, water or water and alcohol, and the alcohol is methanol, ethyl alcohol, any one in isopropanol.

In wherein some embodiments, R₁For ethyl；R₂For ethyl；R₃For carbobenzoxy base.

The present invention also provides a kind of synthetic methods of halofuginone hydrobromide with optical activation.

Specific technical solution is as follows:

A kind of synthetic method of halofuginone hydrobromide with optical activation, includes the following steps:

(3) cis- -2- (2- Chloroallyl) -3- hydroxy piperidine with optical activation in the presence of alkali with amido protecting Reagent reaction, generates the compound of formula (+) -10 with optical activation or formula (-) -10；

(4) compound of formula (+) -10 with optical activation or formula (-) -10 is reacted with alkene bromide reagent and water, Generate the compound of formula (+) -11 with optical activation or formula (-) -11；

(5) compound of formula (+) -11 with optical activation or formula (-) -11 and the compound of formula 12 are under alkali effect Reaction, then slough the 9- fluorenes methoxycarbonyl base protecting group on piperidine ring nitrogen again, generate formula (+) -13 with optical activation or The compound of person's formula (-) -13；

(6) isomerization reaction occurs for the compound of formula (+) -13 with optical activation or formula (-) -13, and generation has Optically active halofuginone hydrobromide；

The halofuginone hydrobromide with optical activation has structure shown in formula (+) -1 or formula (-) -1, and reaction equation is as follows:

Alternatively,

In wherein some embodiments, alkali described in step (3) is selected from sodium carbonate, sodium bicarbonate, potassium carbonate, saleratus In any one.

In wherein some embodiments, amido protecting agent described in step (3) is selected from chloro-carbonic acid -9- fluorenyl methyl ester, 9- Any one in fluorenyl methyl -1- benzotriazole base carbonic ester, 9- fluorene methyl-N- succinimidyl carbonate.

In wherein some embodiments, the solvent of step (3) described reaction is the combination of organic solvent and water, described organic Solvent is Isosorbide-5-Nitrae-dioxane, any one in tetrahydrofuran.

In wherein some embodiments, step (3) alkali, amido protecting agent and cis- -2- (2- Chloroallyl) -3- The molar ratio of hydroxy piperidine is 1~5:1~2:1.

In wherein some embodiments, the temperature of step (3) described reaction is 0~20 DEG C.

In wherein some embodiments, alkene bromide reagent described in step (4) is selected from N- bromo-succinimide, 1,3- Any one in two bromo- 5,5- Dimethyl Hydan.

In wherein some embodiments, the solvent of step (4) described reaction is selected from acetonitrile, tetrahydrofuran, Isosorbide-5-Nitrae-dioxy six Any one in ring.

In wherein some embodiments, alkene bromide reagent described in step (4) and formula (+) -10 or formula (-) -10 The molar ratio of compound is 0.9~1.2:1.

In wherein some embodiments, the reaction temperature of step (4) described reaction is -10~35 DEG C.

In wherein some embodiments, the reaction temperature of the reaction is -10~10 DEG C.

In wherein some embodiments, alkali described in step (5) is selected from potassium carbonate, sodium carbonate, sodium hydroxide, hydroxide Potassium, lithium hydroxide, cesium hydroxide, cesium carbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, lithium hydride, two Isopropylamino lithium, bis- (trimethyl silicon substrate) Sodamides, bis- (trimethyl silicon substrate) lithium amides, in bis- (trimethyl silicon substrate) potassamides Any one.

In wherein some embodiments, the solvent of step (5) described reaction is selected from acetonitrile, methanol, ethyl alcohol, N, N- dimethyl Acetamide, n,N-Dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, toluene, methylene chloride, 1,2- bis- Any one in chloroethanes.

In wherein some embodiments, the change of the compound, formula 12 of formula (+) -11 described in step (5) or formula (-) -11 The molar ratio for closing object and the alkali is 0.8~1.2:1:1~2.

In wherein some embodiments, the reaction temperature of step (5) described reaction is -10~25 DEG C.

In wherein some embodiments, step (5) the 9- fluorenes methoxycarbonyl base protecting group for sloughing nitrogen on piperidine ring is It is carried out under the action of second level organic amine or three-level organic amine.

In wherein some embodiments, step (5) the 9- fluorenes methoxycarbonyl base protecting group for sloughing nitrogen on piperidine ring Reaction temperature is -10~25 DEG C.

In wherein some embodiments, step (5) the second level organic amine or three-level organic amine are diethylamine.

In wherein some embodiments, the solvent of isomerization reaction described in step (6) is selected from water, ethyl alcohol, methanol, positive fourth Alcohol, normal propyl alcohol, the tert-butyl alcohol, n,N-Dimethylformamide, the group of tetrahydrofuran, any one or two kinds in Isosorbide-5-Nitrae-dioxane It closes.

In wherein some embodiments, the reaction temperature of isomerization reaction described in step (6) is 50~80 DEG C.

In wherein some embodiments, the synthetic method of the halofuginone hydrobromide with optical activation further includes that preparation has light The step of learning active cis- -2- (2- Chloroallyl) -3- hydroxy piperidine, comprising:

Cis- -2- (2- the Chloroallyl) -3- hydroxy piperidine of the racemization has structure shown in formula (±) -9；The optics Active cis- -2- (2- Chloroallyl) -3- hydroxy piperidine has structure shown in formula (+) -9 or formula (-) -9；The hexichol first Acyl tartaric acid or derivatives thereof has structure shown in formula 15 or formula 16；The chirality double salt has knot shown in formula 14 or formula 17 Structure；Reaction equation is as follows:

Alternatively,

Wherein, each R is separately selected from: hydrogen or C₁-C₄Alkoxy.

In wherein some embodiments, the recrystallization is in the mixed of the third organic solvent and water that volume ratio is 1:3-5 It is carried out in bonding solvent；The third organic solvent is acetonitrile.

Reaction equation is as follows:

Wherein:

R₂It is selected from: methyl, ethyl；

It is to be appreciated that the above synthesis has the method for have optically active halofuginone hydrobromide, can using step (a) to (g) with (1) it is optically active to synthesize tool as raw material directly to carry out subsequent reaction for any resulting reaction product of a step to (6) Halofuginone hydrobromide.For example, cis- -2- (2- the Chloroallyl) -3- hydroxy piperidine of racemization can be used as raw material and carried out as described above The step of (1) the optically active halofuginone hydrobromide of tool is synthesized to (6), or institute as above as raw material and is carried out using the compound of formula 3 (c) to (g) and (1) stated synthesizes the optically active halofuginone hydrobromide of tool to (6).

The dibenzoyl tartaric acid that the present invention passes through cis- -2- (2- Chloroallyl) -3- hydroxy piperidine chirality of racemization It carries out chiral resolution and has obtained cis- -2- with optical activation (2- Chloroallyl) -3- hydroxy piperidine, the light obtained with fractionation It learns active cis- -2- (2- Chloroallyl) -3- hydroxy piperidine and optically active halofuginone hydrobromide has further been prepared.Cis-- The basic nitrogen atom of 2- (2- Chloroallyl) -3- hydroxy piperidine can lead to chiral dibenzoyl tartaric acid at salt at after salt Crossing simple crystallization fractionation can be obtained cis- -2- with optical activation (2- Chloroallyl) -3- hydroxy piperidine.Of the invention Chiral benzhydryl formyl tartaric acid used in synthetic method is from a wealth of sources, cheap, and preparation process is simple, impurity in products Less, it is not necessarily to column chromatographic purifying, and can realize the large-scale production and preparation of high-optical-purity halofuginone hydrobromide.Chiral halofuginone hydrobromide of the invention And its synthetic method of intermediate solves the technological deficiency in current halofuginone hydrobromide synthesis, synthesis technology is simple, at low cost, synthesis Byproduct in process object is few, and purifying process is simple, is not necessarily to column chromatographic purifying, and product yield high, impurity is few, with high purity, product quality Controllably, synthetic route is cumbersome when and solving existing synthesizing optical activity halofuginone hydrobromide or orixine, severe reaction conditions, receipts Rate is low, it is complicated to isolate and purify or disadvantage using severe toxicity, expensive reagent etc..

Further, it was found by the inventors of the present invention that the reasonable selection of the protecting group of piperidines theheterocyclic nitrogen atom is in halofuginone hydrobromide It is extremely important in synthesis, if protecting group selection is improper, many by-products can be generated during deprotection, will lead to product The low perhaps product quality of yield is bad or purification difficult.The present invention selects 9- fluorenes methoxycarbonyl base (Fmoc) as piperidines The protecting group of theheterocyclic nitrogen atom removes very simple, it is only necessary to several seconds or a few minutes energy are acted in second level or three-level organic amine Removing, greatly reduces the generation of by-product, and present invention employs the synthetic strategies entirely different with the prior art to synthesize often The intermediate of mountain ketone, synthesis technology is simple, at low cost, and by-product is few in synthesis process, and purifying process is simple, chromatographs without column pure Change, product yield high.

Specific embodiment

It is further described in detail below in conjunction with preparation method of the specific embodiment to halofuginone hydrobromide of the invention.

In the present invention, formula 8, formula 9, formula 10, formula 11, formula 13 and 1 compound represented of formula are not marking (+) or (-) When, or at mark (±) be all raceme compound, the stereochemical structure in formula is relative configuration, rather than absolute configuration；When When formula 8, formula 9, formula 10, formula 11, formula 13 and 1 compound represented of formula are labeled with (+) or (-), all there is optically active Chipal compounds, the stereochemical structure in formula is absolute configuration.

The temperature range of room temperature in following embodiment is 18-25 DEG C.

The synthesis of 1 racemization halofuginone hydrobromide of embodiment

4 (R of midbody compound₁=Et) synthesis

Step (a): at room temperature, into 50L reaction kettle be added acetamino diethyl malonate (5.00kg, 23.02mol), Anhydrous potassium carbonate (6.35kg, 46.04mol), potassium iodide (0.76kg, 4.6mol), tetrabutylammonium bromide 2,3- dichloropropylene (3.07kg, 27.62mol) is added in (0.37kg, 1.15mol) and acetonitrile (25L), stirring after twenty minutes.It rises Temperature to 85~90 DEG C of reactions, HPLC monitoring is reacted.After reaction, reaction solution is cooled within 25 DEG C, is slowly dripped to reaction kettle Dilute hydrochloric acid is neutralized to pH7~7.5.It stands, liquid separation, organic layer is concentrated under reduced pressure at 50 DEG C.Condensate residue addition alcohol-water (1: 10,20L) 1 hour crystallization is stirred.It is filtered under diminished pressure, filter cake is eluted with water, obtains yellow solid, the i.e. compound (weight in wet base of formula 2 10.50kg), it does not dry, direct plunges into the next step.

¹H NMR (500MHz, Chloroform-d) δ 5.28 (d, J=1.2Hz, 1H), 5.17 (d, J=1.1Hz, 1H), 4.26 (qd, J=7.1,2.4Hz, 4H), 3.47 (s, 2H), 2.03 (s, 3H), 1.55-1.51 (m, 1H), 1.27 (t, J= 7.1Hz,6H).

¹³C NMR(126MHz,Chloroform-d)δ169.3,167.3,136.5,117.8,65.2,63.0,41.6, 23.0,14.0.

HRMS(m/z):calc.for C₁₂H₁₉ClNO₅[M+H]⁺=292.0952；found,292.0954

Step (b): at room temperature, into 100L reaction kettle, be added formula 2 compound (weight in wet base 10.5kg, 23.02mol) and Hydrochloric acid solution (6mol/L, 57.5L, 345.27mol) stirs and is warming up to 100 DEG C of back flow reactions, TLC monitoring reaction.Reaction knot Shu Houxiang reaction kettle is added activated carbon (650g) and is cooled within 50 DEG C, is filtered under diminished pressure, filter cake is eluted with water, merging filtrate. Filtrate removes solvent in 80~85 DEG C of reduced pressures and obtains faint yellow solid, the i.e. compound (4.05kg) of formula 3, and product is not necessarily into one Step purifying, direct plunges into the next step.

Step (c): at room temperature, into 50L reaction kettle, the compound (4.05kg, 21.77mol) and carbonic acid two of formula 3 is added Ethyl ester (12L) and dehydrated alcohol (4L), stirring.It is added dropwise the concentrated sulfuric acid (1.13kg, 11.51mol), drips off within about 20~30 minutes.Drop Finish, is warming up to 85~95 DEG C of back flow reactions, HPLC monitoring reaction.After reaction, reaction solution is cooled within 50~60 DEG C and subtracts Pressure concentration, remaining liq are diluted with water and are cooled within 10 DEG C.30% sodium hydroxide tune pH8~9 are added dropwise to move back to room temperature, use Methylene chloride (10L × 3) extraction, merges organic layer, and it is dry that anhydrous sodium sulfate is added.It is filtered under diminished pressure, filtrate is dense in 40 DEG C of decompressions Contract to obtain light brown grease, i.e. compound 4 (3.07kg, 3 step yields 75%).

¹H NMR (500MHz, Chloroform-d) δ 5.30 (d, J=1.3Hz, 1H), 5.26 (q, J=1.1Hz, 1H), 4.20 (q, J=7.1Hz, 2H), 3.78 (dd, J=8.6,4.8Hz, 1H), 2.81 (ddd, J=14.2,4.8,1.1Hz, 1H), 2.56 (dd, J=14.2,8.6Hz, 1H), 1.28 (t, J=7.1Hz, 3H)

¹³C NMR(126MHz,Chloroform-d)δ174.5,138.5,115.9,61.4,52.3,44.6,14.3.

HRMS(m/z):calc.for C₇H₁₃ClNO₂[M+H]⁺=178.0635；found,178.0628.

Illustrate: in step (a), product is undried wet product, is more than theoretical value when calculating yield, therefore press 100% calculation of yield, the molal quantity of the compound of formula 2 are 23.02mol.

6 (R of midbody compound₁=Et；R₂=Et；R₃=Cbz) synthesis

Step (d): at room temperature, into 50L reaction kettle, compound (3.07kg, 17.26mol), the anhydrous carbon of formula 4 is added Sour sodium (5.49kg, 51.79mol), tetrabutylammonium iodide (0.64kg, 1.73mol) and toluene (9L), stirring are added after twenty minutes Toluene (6L) solution of 4- bromobutyrate (3.37kg, 17.26mol).It is warming up to 75~80 DEG C to be stirred to react, HPLC monitoring is anti- It answers.After reaction, 20~25 DEG C are cooled to.Water (9L) is added to stir 10~15 minutes, dropwise addition benzyl chloroformate (2.94kg, 17.26mol), it drips off within about 2~3 hours.Drop finishes, and continuation is stirred to react at 20~25 DEG C, TLC monitoring reaction.After reaction plus Water (10L) and toluene (10L) stir 0.5 hour, liquid separation.Organic layer successively uses 5%NaOH (15L), water (20L), 5% hydrochloric acid The washing of (15L), water (20L).Organic layer is stirred at room temperature 1 hour after active carbon (250.0g) is added.It filters, filtrate is at 60 DEG C It is concentrated under reduced pressure, obtains brown oil, i.e. compound 5 (8.10kg), product direct plunges into the next step without being further purified.

¹H NMR (500MHz, Chloroform-d) δ 7.39-7.27 (m, 5H), 5.19 (d, J=1.3Hz, 1H), 5.17- 5.07(m,2.6H),5.02(s,0.4H),4.27–3.89(m,5H),3.68–3.56(m,1H),3.23–3.10(m,1.6H), 3.02-2.90 (m, 1.4H), 2.47-2.26 (m, 2H), 1.99-(m, 2H), 1.27-1.17 (m, 4.8H), 1.13 (t, J= 7.2Hz,1.2H).

¹³C NMR(126MHz,Chloroform-d)δ173.3,173.2,170.3,170.2,155.6,138.8, 138.4,136.7,136.2,128.7,128.6,128.4,128.2,127.9,116.3,116.0,67.6,67.4,61.7, 60.5,59.6,58.7,49.2,48.9,40.5,39.4,31.6,31.4,24.2,23.7,14.4,14.14,14.07.

HRMS(m/z):calc.for C₂₁H₂₉ClNO₆[M+H]⁺=426.1683；found,426.1678

Step (e): it under room temperature and nitrogen protection into 100L reaction kettle, is added sodium tert-butoxide (3.31kg, 34.53mol) And anhydrous tetrahydro furan (38L), stirring are cooled to -5 DEG C or less.The compound (8.10kg, 17.26mol) of formula 5 is dissolved in tetrahydro It is added dropwise in reaction kettle after furans (15L), process temperature control is added dropwise and is no more than 0 DEG C, drips off within 4~5 hours.Drop finishes, and continues 0~5 DEG C stirring, HPLC monitoring reaction.After reaction, dilute hydrochloric acid is added dropwise into kettle, adjusts pH5~6.Drop finishes, and ethyl acetate is added (10L), is stirred at room temperature, liquid separation, and organic layer is washed with saturated sodium-chloride (20L × 2), aqueous layer with ethyl acetate (10L) extraction one It is secondary.Merge organic layer, active carbon (500g) is added and is stirred at room temperature 1 hour.It filters, filtrate decompression concentration obtains shallow brown oil Shape object, i.e. compound 6 (5.44kg, two step yields 83%).

¹H NMR(500MHz,Chloroform-d)δ12.23(s,1H),7.41–7.28(m,5H),5.27–5.05(m, 4H), 5.01 (s, 0.4H), 4.94-4.82 (m, 0.6H), 4.30 (dd, J=13.6,5.7Hz, 0.6H), 4.23 (q, J= 7.1Hz, 2H), 4.19-4.12 (m, 0.4H), 3.09-2.66 (m, 3H), 2.46-2.23 (m, 2H), 1.30 (t, J=7.1Hz, 3H).

¹³C NMR(126MHz,Chloroform-d)δ172.0,171.9,168.8,168.2,155.2,155.1, 138.4,138.3,136.7,136.3,128.5,128.2,128.0,115.8,115.6,97.7,97.4,67.7,67.5, 61.0,52.7,52.5,41.5,40.7,38.2,37.3,22.8,22.3,14.3.

HRMS(m/z):calc.for C₁₉H₂₃ClNO₅[M+H]⁺=380.1265；found,380.1266

Illustrate: being more than theoretical value when calculating yield, therefore press 100% calculation of yield, the chemical combination of formula 5 in step (d) The molal quantity of object is 17.26mol.

7 (R of midbody compound₃=Cbz) synthesis

Step (f): at room temperature into 50L reaction kettle, be added compound 6 (5.44kg, 14.33mol), DMF (16.3L), Water (2.7L) and lithium chloride (0.61kg, 14.33mol), stirring.It is warming up to 120 DEG C to be stirred to react, HPLC monitoring reaction.Reaction After, reaction solution is cooled to 20~25 DEG C.Water (25L) and methyl tertiary butyl ether(MTBE) (30L) stirring, liquid separation is added.Organic layer is used Water washing (25L × 2) washing, liquid separation.The water layer of generation is extracted with methyl tertiary butyl ether(MTBE) (25L).Merge organic layer, subtracts at 45 DEG C Pressure is concentrated to give brown oil, i.e. compound 7 (4.19kg, yield 95%).

¹H NMR(500MHz,Chloroform-d)δ7.40–7.29(m,5H),5.32–5.03(m,4H),4.86(s, 1H),4.34–3.98(m,1H),3.23(s,1H),2.94–2.59(m,2H),2.59–2.39(m,2H),2.05(s,1H), 2.01–1.92(m,1H).

¹³C NMR(126MHz,Chloroform-d)δ206.7,155.5,128.6,128.3,116.1,67.8,61.8, 37.1,22.5.

HRMS(m/z):calc.for C₁₆H₁₉ClNO₃[M+H]⁺=308.1053；found,308.1057

8 (R of midbody compound₃=Cbz) synthesis

Step (g): be added at room temperature into 50L reaction kettle dehydrated alcohol (18L) and sodium borohydride (0.51kg, 13.61mol), it stirs and is cooled to 5~10 DEG C.Compound 7 (4.19kg, 13.61mol) drips after being dissolved with dehydrated alcohol (9L) It adds in reaction kettle, process temperature control is added dropwise and is no more than 10 DEG C.Drop finishes, and continues to stir at 5~10 DEG C, HPLC monitoring reaction.Reaction After, water (20L) is added dropwise into reaction kettle.Drop finishes, and methyl tertiary butyl ether(MTBE) (25L) stirring, liquid separation is added.Organic layer is used respectively 10%NaOH (10L), 5% hydrochloric acid (10L × 2), water (10L) washing, the water layer of generation are extracted with methyl tertiary butyl ether(MTBE) (25L). Merge organic layer, active carbon (500g) is added and is stirred at room temperature 1 hour.It is filtered under diminished pressure, 45 DEG C of filtrate are concentrated under reduced pressure to obtain brown oil Shape object, i.e. compound 8 (3.50kg, yield 83%).

¹H NMR(500MHz,Chloroform-d)δ7.42–7.27(m,5H),5.21–5.06(m,4H),4.76(s, 1H), 4.05 (d, J=14.0Hz, 1H), 3.92-3.79 (m, 1H), 2.84-2.60 (m, 3H), 1.87-1.76 (m, 1H), 1.76–1.65(m,1H),1.58–1.42(m,2H).

¹³C NMR(126MHz,Chloroform-d)δ155.8,139.8,136.7,128.5,128.2,128.1, 114.5,68.7,67.5,54.2,37.9,33.5,27.9,24.3.

HRMS(m/z):calc.for C₁₆H₂₁ClNO₃[M+H]⁺=310.1210；found,310.1208

The synthesis of midbody compound 9

Step (g): at room temperature into 50L reaction kettle, be added compound 8 (3.55kg, 12.36mol), hydrochloric acid (6mol/L, 18.83L, 112.98mol) and ethyl alcohol (20L), stir and be warming up to back flow reaction, HPLC monitoring reaction.After reaction, instead It answers liquid to be cooled to 50~55 DEG C, is concentrated under reduced pressure and removes ethyl alcohol.Methyl tertiary butyl ether(MTBE) (20L × 2) stirring is added in remaining liq, point Liquid.Ethyl acetate (20L × 2) extraction is added behind 40% sodium hydroxide tune pH > 11 of water layer.Merge organic layer, anhydrous sulphur is added Sour magnesium is dry.Filtering, filtrate decompression are concentrated to give product crude product.Crude product is added acetonitrile (5L) and is stored at room temperature after 70 DEG C of stirring and dissolvings Crystallization.Filtering, vacuum drying, obtains near-white solid, i.e. compound 9 (1.01kg, yield 50.7%).

¹H NMR (500MHz, Chloroform-d) δ 5.25 (d, J=1.1Hz, 1H), 5.23 (t, J=1.0Hz, 1H), 3.65 (S, 1H), 3.03 (ddt, J=11.5,4.3,2.0Hz, 1H), 2.88 (ddd, J=7.5,6.3,1.4Hz, 1H), 2.65 (td, J=11.9,2.9Hz, 1H), 2.49 (d, J=6.8Hz, 2H), 1.91 (dtt, J=13.4,4.0,2.0Hz, 1H), 1.73 (qt, J=13.1,4.3Hz, 1H), 1.54 (tdd, J=13.3,4.7,2.5Hz, 1H), 1.45 (ddq, J=12.9, 4.9,2.6Hz,1H).

¹³C NMR(126MHz,Chloroform-d)δ139.8,115.2,67.1,57.7,47.2,43.0,32.2, 20.4.

HRMS(m/z):calc.for C₈H₁₅ClNO[M+H]⁺=176.0842；found,176.0837

The synthesis of midbody compound 13

Step (i): at room temperature into 50L reaction kettle be added compound 9 (1kg, 5.69mol), Isosorbide-5-Nitrae-dioxane (5L), Water (5L), sodium carbonate (0.91kg, 8.54mol), stir and are cooled to 5~10 DEG C.Chloro-carbonic acid -9- fluorenyl methyl ester (1.47kg, It is added dropwise in reaction kettle after 5.69mol) being dissolved in Isosorbide-5-Nitrae-dioxane (2L), temperature control is no more than 20 DEG C.Drop finishes, and continuation is stirred in room temperature Mix reaction, TLC monitoring.After reaction, ethyl acetate (20L) and water (20L) stirring, liquid separation is added.Organic layer saturation chlorine Change sodium (5L × 2) washing, liquid separation.Aqueous layer with ethyl acetate (10L) extraction is primary.Merge organic layer, is added active carbon (500g) It is stirred at room temperature 1 hour.Filtering, filtrate decompression are concentrated to give faint yellow thick liquid, i.e. compound 10 (2.81kg), and product is not necessarily into one Step purifying, direct plunges into the next step.

¹H NMR(500MHz,Chloroform-d)δ7.81–7.71(m,2H),7.65–7.53(m,2H),7.40(td,J =7.5,2.4Hz, 2H), 7.31 (t, J=7.4Hz, 2H), 5.17 (s, 1H), 5.14 (s, 1H), 4.93-4.51 (m, 1H), 4.49 (dd, J=10.7,6.7Hz, 1H), 4.41 (dd, J=10.7,6.5Hz, 1H), 4.25 (t, J=6.5Hz, 1H), 3.92 (s,1H),3.76(s,1H),2.85–2.54(m,3H),1.87–1.74(m,1H),1.73–1.58(m,1H),1.57–1.33 (m,2H).

¹³C NMR(126MHz,Chloroform-d)δ155.8,144.1,141.5,141.4,139.8,127.73, 127.70,127.15,127.10,125.09,125.06,120.02,119.99,114.4,68.4,67.5,54.3,47.5, 37.9,33.3,27.7,24.2.

HRMS(m/z):calc.for C₂₃H₂₅ClNO₃[M+H]⁺=398.1523；found,398.1530

Step (j): at room temperature to 50L reaction kettle, compound 10 (2.81kg, 5.69mol), acetonitrile (10L) and water is added (5L) is stirred and is cooled to 0~5 DEG C.N- bromo-succinimide (1.01kg, 5.69mol) is added portionwise in reaction kettle, temperature control No more than 5 DEG C.It finishes, continuation is stirred to react at 0~5 DEG C, HPLC monitoring reaction.After reaction, 10% sodium sulfite is added Solution (10L) stirs 0.5 hour.Ethyl acetate (10L × 2) are added and extract liquid separation.Organic layer uses saturated sodium bicarbonate respectively (5L), saturated sodium-chloride (5L × 2) wash liquid separation.After organic layer addition active carbon (320g) is stirred at room temperature 1 hour, it is added anhydrous Magnesium sulfate continues stirring 0.5 hour.Filtering, filtrate decompression are concentrated to give thick liquid, i.e. compound 11 (2.85kg), product be not necessarily into The purifying of one step, direct plunges into the next step.

Illustrate: being more than theoretical value when calculating yield, therefore press 100% calculation of yield, the change of formula 10 in step (i) The molal quantity for closing object is 5.69mol.

Step (k): at room temperature to 100L reaction kettle, compound 12 (1.40kg, 5.41mol), lithium hydroxide is added (0.15kg, 6.26mol), n,N-Dimethylformamide (28L), is cooled to 0~5 DEG C after being stirred at room temperature 1 hour.Compound 11 (2.85kg, 5.69mol) is added dropwise in reaction kettle after being dissolved in n,N-Dimethylformamide (2.8L), and temperature control is no more than 5 DEG C, 4~5 Hour drips off.Drop finishes, and continues to stir at 0~5 DEG C, HPLC monitoring reaction.After reaction, diethylamine is added to reaction kettle (1L), and continue to stir at 0~5 DEG C, HPLC monitoring reaction.After reaction, water (25L) and ethyl acetate is added to reaction kettle (30L) stirs liquid separation.Aqueous layer with ethyl acetate (20L × 3) extraction.Merge organic layer, 50 DEG C of reduced pressures.Condensate residue 85% lactic acid solution (1.5kg) is added, methyl tertiary butyl ether(MTBE) (10L × 2) extraction is added after being stirred at room temperature 1 hour, water layer is added Potassium carbonate tune pH8~9.Ethyl acetate (15L × 3) extraction is added, merges organic layer, 45~50 DEG C are concentrated under reduced pressure to obtain crude product.Slightly Product are added after ethyl acetate (8L) is stirred at room temperature 0.5 hour and filter, the vacuum drying white solid of filter cake, compound 13 (1.84kg, 3 step yields 78%).

¹H NMR(400MHz,Chloroform-d)δ8.32(s,1H),8.26(s,1H),7.98(s,1H),4.34(d,J =13.9Hz, 1H), 4.16 (d, J=13.9Hz, 1H), 3.88 (t, J=3.1Hz, 1H), 3.29 (t, J=3.4Hz, 1H), 2.97 (d, J=10.9Hz, 1H), 2.52 (t, J=11.8Hz, 1H), 2.10 (d, J=15.1Hz, 1H), 2.03 (dd, J= 13.1,3.7Hz, 2H), 1.83 (d, J=13.2Hz, 1H), 1.81-1.72 (m, 1H), 1.54 (ddt, J=15.0,12.0, 3.4Hz,2H).

¹³C NMR(126MHz,Chloroform-d)δ160.1,149.5,147.2,133.4,132.7,129.4, 127.9,122.1,105.3,78.0,55.8,50.3,44.67,43.7,26.9,20.2.

HRMS(m/z):calc.for C₁₆H₁₈BrClN₃O₃[M+H]⁺=414.0220/416.0200；found, 414.0216/416.0197

Illustrate: in step (i) and (j), above theoretical value when calculating yield, therefore press 100% calculation of yield, formula The molal quantity of 11 compound is 5.69mol.

The synthesis of racemization halofuginone hydrobromide (compound 1)

Step (l): at room temperature to 50L reaction kettle, compound 13 (1.84kg, 4.43mol) and dehydrated alcohol (20L) is added It is stirred and heated to back flow reaction, HPLC monitoring reaction.After reaction, reaction solution is cooled to 55~60 DEG C.It is filtered under diminished pressure, second Alcohol elution, filter cake vacuum drying, obtains white solid, i.e. compound 1 (1.31kg, yield 71.2%, HPLC purity 98.6%).

¹H NMR(400MHz,DMSO-d₆) δ 8.23 (s, 1H), 8.22 (s, 1H), 8.15 (s, 1H), 4.99 (d, J= 2.8Hz, 2H), 4.79 (d, J=5.8Hz, 1H), 2.98 (dt, J=15.3,4.7Hz, 2H), 2.78 (d, J=12.3Hz, 1H), 2.64 (td, J=8.9,3.8Hz, 1H), 2.44 (dd, J=15.5,8.7Hz, 1H), 2.36 (td, J=12.1,2.7Hz, 1H), 1.95-1.83 (m, 1H), 1.56 (dt, J=13.3,3.2Hz, 1H), 1.34 (qt, J=12.4,3.7Hz, 1H), 1.28-1.13 (m,1H).

¹³C NMR(126MHz,DMSO-d₆)δ200.7,158.6,149.5,147.2,132.4,131.8,128.4, 126.8,121.7,66.7,56.2,54.4,43.0,30.5,20.1.

HRMS(m/z):calc.for C₁₆H₁₈BrClN₃O₃[M+H]⁺=414.0220/416.0200；found, 414.0214/416.0195

Embodiment 2

Compound (optically active [(+)-(2S, 3S) -2- (2- Chloroallyl) -3- hydroxyl piperazine of dextrorotation of formula (+) -9 Pyridine]) synthesis

Step (1): at room temperature, compound (140g, the 0.797mol, according to reality of the formula 9 of racemization are added into 5L there-necked flask Apply the method preparation of example 1) and acetonitrile (1400ml), it is heated to 60 DEG C of stirring and dissolvings.L- (-)-dibenzoyl tartaric acid of formula 15 (300g, 0.837mol) is added dropwise in reaction flask after being dissolved in acetonitrile (800ml), is dripped off within about 10 minutes.Drop finishes, and stirs 20~30 points Zhong Hou is moved to and is stirred at room temperature 2 hours.Filtering, acetonitrile (300ml) elution, drains to obtain double salt crude product.Pure water-acetonitrile is added in crude product (1:4,2000ml), stirring are filtered, 2 hours crystallizations are stirred at room temperature in filtrate while hot after being heated to 80 DEG C of dissolutions.Filtering, acetonitrile Elution, it is dry, obtain double salt highly finished product, the i.e. compound (136g, yield 32%) of formula 14.

Step (2): at room temperature, the compound (136g) of formula 14, pure water (700ml) and acetic acid second are added into 5L there-necked flask 1mol/L NaOH tune pH12~14 are added dropwise in ester (700ml), stirring.Liquid separation, aqueous layer with ethyl acetate (700ml × 2) extraction, is closed And organic layer, anhydrous MgSO is added₄It dries, filters, filtrate is concentrated under reduced pressure at 50 DEG C, obtains white solid, i.e. compound (+) -9 (44g, yield 98%).

[α]_D=+8.43 ° (c=0.46, MeOH)

¹³C NMR(126MHz,Chloroform-d)δ139.8,115.2,67.1,57.7,47.2,43.0,32.2, 20.4.

HRMS(m/z):calc.for C₈H₁₅ClNO[M+H]⁺=176.0842；found,176.0837

Embodiment 3

Compound (left-handed optically active [(-)-(2R, 3R) -2- (2- Chloroallyl) -3- hydroxyl piperazine of formula (-) -9 Pyridine]) synthesis

Step (1): at room temperature, compound (14g, the 79.7mmol, according to reality of the formula 9 of racemization are added into 5L there-necked flask Apply the method preparation of example 1) and acetonitrile (140ml), it is heated to 60 DEG C of stirring and dissolvings.L- (-)-dibenzoyl tartaric acid of formula 16 (30g, 83.7mmol) is added dropwise in reaction flask after being dissolved in acetonitrile (80ml), is dripped off within about 10 minutes.Drop finishes, and stirs 20~30 minutes Afterwards, it moves to and is stirred at room temperature 2 hours.Filtering, acetonitrile (30ml) elution, drains to obtain double salt crude product.Crude product addition pure water-acetonitrile (1: 4,200ml) it, stirs, after being heated to 80 DEG C of dissolutions, filters while hot, 2 hours crystallizations are stirred at room temperature in filtrate.Filtering, acetonitrile leaching It washes, it is dry, obtain double salt highly finished product, the i.e. compound (12.1g, yield 28.4%) of formula 17.

Step (2): at room temperature, the compound (12.1g) of formula 17, pure water (70ml) and acetic acid second are added into 5L there-necked flask 1mol/L NaOH tune pH12~14 are added dropwise in ester (100ml), stirring.Liquid separation, aqueous layer with ethyl acetate (100ml × 2) extraction, is closed And organic layer, anhydrous MgSO is added₄It dries, filters, filtrate is concentrated under reduced pressure at 50 DEG C, obtains white solid, i.e. compound (-) -9 (3.7g, yield 93.1%).

[α]_D=-8.43 ° (c=0.46, MeOH)

¹³C NMR(126MHz,Chloroform-d)δ139.8,115.2,67.1,57.7,47.2,43.0,32.2, 20.4.

HRMS(m/z):calc.for C₈H₁₅ClNO[M+H]⁺=176.0842；found,176.0837

4 compound (+) -1 of embodiment, the i.e. preparation of (+)-halofuginone hydrobromide (dextrorotation halofuginone hydrobromide)

Step (3): compound (+) -9 (10g, 56.9mmol), Isosorbide-5-Nitrae-dioxy six is added into 500mL reaction flask at room temperature Ring (50mL), water (50mL), sodium carbonate (9.1g, 85.4mmol), stir and are cooled to 5~10 DEG C.Chloro-carbonic acid -9- fluorenyl methyl ester (14.7g, 56.9mmol) is added dropwise in reaction flask after being dissolved in Isosorbide-5-Nitrae-dioxane (20mL), and temperature control is no more than 20 DEG C.Drop finishes, after It is continuous that reaction, TLC monitoring is stirred at room temperature.After reaction, ethyl acetate (200mL) and water (200mL) stirring, liquid separation is added. Organic layer is washed with saturated sodium-chloride (50mL × 2), liquid separation.Aqueous layer with ethyl acetate (100mL) extraction is primary.Merge organic Layer is added active carbon (5g) and is stirred at room temperature 1 hour.Filtering, filtrate decompression are concentrated to give faint yellow thick liquid, i.e. compound (+) -10 (25.1g, ee=96%), product direct plunge into the next step without being further purified.

[α]_D=+25.42 ° of (c=0.35, CHCl₃)

HRMS(m/z):calc.for C₂₃H₂₅ClNO₃[M+H]⁺=398.1523；found,398.1530

Step (4): at room temperature to 500mL reaction flask, compound (+) -10 (28g, 56.9mol), acetonitrile (100mL) is added With water (50mL), stirs and be cooled to 0~5 DEG C.Reaction flask is added portionwise in N- bromo-succinimide (10.1g, 56.9mol) In, temperature control is no more than 5 DEG C.It finishes, continuation is stirred to react at 0~5 DEG C, HPLC monitoring reaction.After reaction, it is sub- to be added 10% Metabisulfite solution (100mL) stirs 0.5 hour.Ethyl acetate (100mL × 2) are added and extract liquid separation.Organic layer is respectively with saturation Sodium bicarbonate (50mL), saturated sodium-chloride (50mL × 2) wash liquid separation.Organic layer is added active carbon (5g) and is stirred at room temperature 1 hour Afterwards, anhydrous magnesium sulfate is added and continues stirring 0.5 hour.Filtering, filtrate decompression are concentrated to give thick liquid, i.e. compound (+) -11 [27.5g,[α]_D=+36.66 ° of (c=0.30, CHCl₃)], product direct plunges into the next step without being further purified.

Step (5): at room temperature to 1000mL reaction flask, be added compound 12 (14g, 54.1mol), lithium hydroxide (1.5g, 62.6mol), n,N-Dimethylformamide (280mL) is cooled to 0~5 DEG C after being stirred at room temperature 1 hour.Compound (+) -11 (27.5g, 56.9mol) is added dropwise in reaction kettle after being dissolved in n,N-Dimethylformamide (30mL), and temperature control is no more than 5 DEG C, 4~5 Hour drips off.Drop finishes, and continues to stir at 0~5 DEG C, HPLC monitoring reaction.After reaction, diethylamine is added to reaction kettle (10mL), and continue to stir at 0~5 DEG C, HPLC monitoring reaction.After reaction, water (250mL) and acetic acid is added to reaction kettle Ethyl ester (300mL) stirs liquid separation.Aqueous layer with ethyl acetate (200mL × 3) extraction merges organic layer, 50 DEG C of reduced pressures.It is dense 85% lactic acid solution (15g) is added in contracting residue, and methyl tertiary butyl ether(MTBE) (100mL × 2) extraction is added after being stirred at room temperature 1 hour, Water layer is extracted after potassium carbonate tune pH8~9 are added with ethyl acetate (150mL × 3), merges organic layer, 45~50 DEG C of reduced pressures Obtain crude product.Crude product is added after ethyl acetate (80mL) is stirred at room temperature 0.5 hour and filters, and filter cake is dried in vacuo to obtain white solid, changes It closes object (+) -13 (16.8g, 3 step yields 71%).

[α]_D=+81.21 ° of (c=0.52, CHCl₃)

¹H NMR(400MHz,Chloroform-d)δ8.32(s,1H),8.26(s,1H),7.98(s,1H),4.34(d,J =13.9Hz, 1H), 4.16 (d, J=13.9Hz, 1H), 3.88 (t, J=3.1Hz, 1H), 3.29 (t, J=3.4Hz, 1H), (2.97 d, J=10.9Hz, 1H), 2.52 (t, J=11.8Hz, 1H), 2.10 (d, J=15.1Hz, 1H), 2.03 (dd, J= 13.1,3.7Hz, 2H), 1.83 (d, J=13.2Hz, 1H), 1.81-1.72 (m, 1H), 1.54 (ddt, J=15.0,12.0, 3.4Hz,2H).

Step (6): at room temperature to 500mL reaction flask, compound (+) -13 (15g, 36.17mmol) and dehydrated alcohol is added (150mL) is stirred and heated to back flow reaction, HPLC monitoring reaction.After reaction, reaction solution is cooled to 55~60 DEG C.Decompression Filtering, ethanol rinse, filter cake vacuum drying obtain white solid, i.e. (+)-halofuginone hydrobromide (12.1g, yield 80.6%, HPLC purity 98.5%, ee=99.6%).

[α]_D=+18.52 ° (c=0.53, DMSO)

Each technical characteristic of embodiment described above can be combined arbitrarily, for simplicity of description, not to above-mentioned reality It applies all possible combination of each technical characteristic in example to be all described, as long as however, the combination of these technical characteristics is not deposited In contradiction, all should be considered as described in this specification.

The embodiments described above only express several embodiments of the present invention, and the description thereof is more specific and detailed, but simultaneously It cannot therefore be construed as limiting the scope of the patent.It should be pointed out that coming for those of ordinary skill in the art It says, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to protection of the invention Range.Therefore, the scope of protection of the patent of the invention shall be subject to the appended claims.

Claims

1. a kind of preparation method of cis- -2- (2- Chloroallyl) -3- hydroxy piperidine with optical activation, which is characterized in that Include the following steps:

(1) in the first organic solvent, by cis- -2- (2- the Chloroallyl) -3- hydroxy piperidine and Dibenzoyl tartaric of racemization Acid or derivatives thereof carries out salt-forming reaction and generates precipitating, and the precipitating is recrystallized, chiral double salt is obtained；

(2) in a second organic solvent, the chiral double salt is neutralized to alkalinity with alkaline aqueous solution, obtained with optical activity Cis- -2- (2- Chloroallyl) -3- hydroxy piperidine；

Cis- -2- (2- the Chloroallyl) -3- hydroxy piperidine of the racemization has structure shown in formula (±) -9；It is described that there is optics Active cis- -2- (2- Chloroallyl) -3- hydroxy piperidine has structure shown in formula (+) -9 or formula (-) -9；The hexichol first Acyl tartaric acid or derivatives thereof has structure shown in formula 15 or formula 16；The chirality double salt has knot shown in formula 14 or formula 17 Structure；Reaction equation is as follows:

Alternatively,

Wherein, each R is separately selected from: hydrogen or C₁-C₄Alkoxy.

2. the preparation side of cis- -2- (2- Chloroallyl) -3- hydroxy piperidine with optical activation according to claim 1 Method, which is characterized in that the dibenzoyl tartaric acid or derivatives thereof of formula 15 described in step (1) is L- (-)-dibenzoyl wine Stone acid or L- (-)-di-p-methoxy benzoyltartaric acid, the dibenzoyl tartaric acid or derivatives thereof of formula 16 is D- (+)-hexichol Formyl tartaric acid or D- (+)-di-p-methoxy benzoyltartaric acid.

3. the preparation side of cis- -2- (2- Chloroallyl) -3- hydroxy piperidine with optical activation according to claim 1 Method, which is characterized in that cis- -2- (2- the Chloroallyl) -3- hydroxy piperidine and dibenzoyl wine of racemization described in step (1) The molar ratio of stone acid or derivatives thereof is 1:1~2.

4. the preparation side of cis- -2- (2- Chloroallyl) -3- hydroxy piperidine with optical activation according to claim 1 Method, which is characterized in that it is described recrystallization be volume ratio be 1~10:1 third organic solvent and water in the mixed solvent into Row；The third organic solvent in ethyl alcohol, methanol, isopropanol, acetonitrile, Isosorbide-5-Nitrae-dioxane and acetone any one or It is a variety of.

5. the preparation side of cis- -2- (2- Chloroallyl) -3- hydroxy piperidine with optical activation according to claim 1 Method, which is characterized in that the first organic solvent described in step (1) be selected from ethyl alcohol, methanol, isopropanol, acetonitrile, methylene chloride, Isosorbide-5-Nitrae-dioxane, tetrahydrofuran, toluene, acetone, any one or more in ethyl acetate；And/or

Second organic solvent described in step (2) in ethyl acetate, methylene chloride and chloroform any one or It is a variety of.

6. the preparation side of cis- -2- (2- Chloroallyl) -3- hydroxy piperidine with optical activation according to claim 1 Method, which is characterized in that the temperature of the salt-forming reaction is 0~100 DEG C；And/or the temperature of the recrystallization is 0~30 DEG C.

7. the preparation side of cis- -2- (2- Chloroallyl) -3- hydroxy piperidine with optical activation according to claim 1 Method, which is characterized in that alkaline aqueous solution described in step (2) is sodium hydrate aqueous solution, potassium hydroxide aqueous solution, hydroxide Any one in lithium aqueous solution, wet chemical and aqueous sodium carbonate, it is described that be neutralized to alkalinity to be neutralized to pH be 8~ 14。

8. cis- -2- (2- Chloroallyl) -3- hydroxy piperidine with optical activation according to claim 1-7 Preparation method, which is characterized in that the synthetic method of cis- -2- (2- Chloroallyl) -3- hydroxy piperidine of the racemization includes Following steps:

(a) with 2,3- dichloropropylene alkylated reaction occurs for acetamino diethyl malonate under alkali and catalyst action, raw The compound of an accepted way of doing sth 2；

(d) alkylated reaction of nitrogen occurs under the action of alkali and catalyst with the halogenated butyrate of 4- for the compound of formula 4, then again The protection for carrying out nitrogen with amido protecting agent is reacted, the compound of production 5；

Reaction equation is as follows:

Wherein:

R₂It is selected from: methyl, ethyl；

R₃It is selected from: methoxycarbonyl base, ethoxycarbonyl, tertiary fourth oxygen formoxyl, carbobenzoxy base, tri-chloroethoxy formoxyl or benzyl.

9. a kind of synthetic method of halofuginone hydrobromide with optical activation, which comprises the steps of:

(3) cis- -2- (2- Chloroallyl) -3- hydroxy piperidine with optical activation in the presence of alkali with amido protecting agent Reaction, generates the compound of formula (+) -10 with optical activation or formula (-) -10；

(4) compound of formula (+) -10 with optical activation or formula (-) -10 is reacted with alkene bromide reagent and water, is generated The compound of formula (+) -11 with optical activation or formula (-) -11；

(5) compound of formula (+) -11 with optical activation or formula (-) -11 and the compound of formula 12 are anti-under alkali effect Answer, then slough the 9- fluorenes methoxycarbonyl base protecting group on piperidine ring nitrogen again, generate formula (+) -13 with optical activation or The compound of formula (-) -13；

(6) isomerization reaction occurs for the compound of formula (+) -13 with optical activation or formula (-) -13, and generating has optics Active halofuginone hydrobromide；

Alternatively,

10. the synthetic method of halofuginone hydrobromide with optical activation according to claim 9, which is characterized in that step (3) institute Any one of the alkali stated in sodium carbonate, sodium bicarbonate, potassium carbonate, saleratus；And/or

Amido protecting agent described in step (3) is selected from chloro-carbonic acid -9- fluorenyl methyl ester, 9- fluorenyl methyl -1- benzotriazole base carbon Any one in acid esters, 9- fluorene methyl-N- succinimidyl carbonate；And/or

The solvent of step (3) described reaction is the combination of organic solvent and water, and the organic solvent is Isosorbide-5-Nitrae-dioxane, tetrahydro Any one in furans；And/or

The molar ratio of step (3) alkali, amido protecting agent and cis- -2- (2- Chloroallyl) -3- hydroxy piperidine is 1~5: 1~2:1；And/or

The temperature of step (3) described reaction is 0~20 DEG C.

11. the synthetic method of halofuginone hydrobromide with optical activation according to claim 9, which is characterized in that step (4) institute Any one of the alkene bromide reagent stated in N- bromo-succinimide, the bromo- 5,5- Dimethyl Hydan of 1,3- bis-；And/ Or,

Any one of the solvent of step (4) described reaction in acetonitrile, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane；And/or

The molar ratio of the compound of alkene bromide reagent described in step (4) and formula (+) -10 or formula (-) -10 is 0.9~ 1.2:1；And/or

The reaction temperature of step (4) described reaction is -10~35 DEG C.

12. the synthetic method of halofuginone hydrobromide with optical activation according to claim 9, which is characterized in that step (5) institute The alkali stated is selected from potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, cesium carbonate, sodium methoxide, second It is sodium alkoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, lithium hydride, lithium diisopropylamine, bis- (trimethyl silicon substrate) Sodamides, double Any one in (trimethyl silicon substrate) lithium amide, bis- (trimethyl silicon substrate) potassamides；And/or

The solvent of step (5) described reaction is selected from acetonitrile, methanol, ethyl alcohol, DMAC N,N' dimethyl acetamide, N, N- dimethyl formyl Amine, dimethyl sulfoxide, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, toluene, methylene chloride, any one in 1,2- dichloroethanes； And/or

The compound of formula (+) -11 described in step (5) or formula (-) -11, formula 12 the molar ratio of compound and the alkali be 0.8~1.2:1:1~2；And/or

The reaction temperature of step (5) described reaction is -10~25 DEG C；And/or

Sloughing the 9- fluorenes methoxycarbonyl base protecting group of nitrogen on piperidine ring described in step (5) is in second level organic amine or three-level organic amine Under the action of carry out；And/or

The reaction temperature of step (5) the 9- fluorenes methoxycarbonyl base protecting group for sloughing nitrogen on piperidine ring is -10~25 DEG C.

13. the synthetic method of halofuginone hydrobromide with optical activation according to claim 12, which is characterized in that the second level Organic amine or three-level organic amine are diethylamine.

14. the synthetic method of halofuginone hydrobromide with optical activation according to claim 9, which is characterized in that step (6) institute The solvent for the isomerization reaction stated is selected from water, ethyl alcohol, methanol, n-butanol, normal propyl alcohol, the tert-butyl alcohol, N,N-dimethylformamide, four The combination of any one or two kinds in hydrogen furans, Isosorbide-5-Nitrae-dioxane；And/or

The reaction temperature of isomerization reaction described in step (6) is 50~80 DEG C.

15. according to the synthetic method of the described in any item halofuginone hydrobromides with optical activation of claim 9-14, which is characterized in that Further include the steps that preparing cis- -2- with optical activation (2- Chloroallyl) -3- hydroxy piperidine, comprising:

Alternatively,

Wherein, each R is separately selected from: hydrogen or C₁-C₄Alkoxy.

16. the synthetic method of halofuginone hydrobromide with optical activation according to claim 15, which is characterized in that step (1) Described in the dibenzoyl tartaric acid or derivatives thereof of formula 15 be-two pairs of methoxies of L- (-)-dibenzoyl tartaric acid or L- (-) Base benzoyltartaric acid, the dibenzoyl tartaric acid or derivatives thereof of formula 16 is D- (+)-dibenzoyl tartaric acid or D- (+)-two To methoxybenzoyl tartaric acid.

17. the synthetic method of halofuginone hydrobromide with optical activation according to claim 15, which is characterized in that step (1) Described in racemization cis- -2- (2- Chloroallyl) -3- hydroxy piperidine and dibenzoyl tartaric acid or derivatives thereof mole Than being 1:1~2.

18. the synthetic method of halofuginone hydrobromide with optical activation according to claim 15, which is characterized in that the heavy knot Crystalline substance is the in the mixed solvent progress in third organic solvent and water that volume ratio is 1~10:1；The third organic solvent is selected from Ethyl alcohol, methanol, isopropanol, acetonitrile, any one or more in Isosorbide-5-Nitrae-dioxane and acetone.

19. the synthetic method of halofuginone hydrobromide with optical activation according to claim 15, which is characterized in that step (1) Described in the first organic solvent be selected from ethyl alcohol, methanol, isopropanol, acetonitrile, methylene chloride, Isosorbide-5-Nitrae-dioxane, tetrahydrofuran, Toluene, acetone, any one or more in ethyl acetate；And/or

20. the synthetic method of halofuginone hydrobromide with optical activation according to claim 15, which is characterized in that described at salt The temperature of reaction is 0~100 DEG C；And/or the temperature of the recrystallization is 0~30 DEG C.

21. the synthetic method of halofuginone hydrobromide with optical activation according to claim 15, which is characterized in that step (2) Described in alkaline aqueous solution be sodium hydrate aqueous solution, potassium hydroxide aqueous solution, lithium hydroxide aqueous solution, wet chemical With any one in aqueous sodium carbonate, the alkalinity that is neutralized to is to be neutralized to pH be 8~14.

22. the synthetic method of halofuginone hydrobromide with optical activation according to claim 15, which is characterized in that the racemization The synthetic method of cis- -2- (2- Chloroallyl) -3- hydroxy piperidine include the following steps:

Reaction equation is as follows:

Wherein:

R₂It is selected from: methyl, ethyl；