CN102584732B - Method for preparing plerixafor - Google Patents
Method for preparing plerixafor Download PDFInfo
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- CN102584732B CN102584732B CN201110458190.8A CN201110458190A CN102584732B CN 102584732 B CN102584732 B CN 102584732B CN 201110458190 A CN201110458190 A CN 201110458190A CN 102584732 B CN102584732 B CN 102584732B
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Abstract
The invention discloses a method for preparing plerixafor, and particularly discloses a method for synthesizing and purifying plerixafor. The method comprises the following steps of: reacting 1,4,8,11-tetraazacyclic tetradecane serving as a raw material with paratoluensulfonyl chloride, segmentally crystalizing and purifying, and undergoing a bridging reaction with alpha,alpha'-dibromopxylene in anhydrous acetonitrile under the action of an acid-binding agent; and performing deprotection in a mixed acid to obtain crude plerixafor, and refining to obtain a target product. Due to the adoption of the method, the problems of the use of column purification, complex post-treatment and low yield existing in the prior art are solved; in particular, a segmental crystalizing method is adopted, so that impurities are removed effectively, the purity of an obtained product is higher than 99.5 percent, and the single impurity content is less than 0.1 percent; and moreover, the method is easy and convenient to operate, has a short production period, and is easy for realizing mass production.
Description
Technical field
The present invention relates to organic synthesis field, a kind of preparation method of high purity Plerixafor, the particularly purifying of intermediate,, segmentation crystallization removal of impurities refining with mixed solvent etc.
Background technology
Plerixafor, chinesization formal name used at school: 1,1 '-[Isosorbide-5-Nitrae-phenylene two (methylene radical)]-bis--Isosorbide-5-Nitrae, 8,11-tetraazacyclododecane tetradecane, chemical structural formula is:
Plerixafor (trade(brand)name Mozobil
tM) be the specificity antagonism of the Chemokine Receptors 4 (CXCR4) of U.S. Genzyme company research and development.This medicine is a kind of Hematopoietic Stem (ancestral) cell activator, simultaneously can hemopoietic stem cells hyperplasia, differentiation enters sanguimotor function.
Because non-Hodgkin lymphoma (NHL) and multiple myeloma (MM) SPR case and progress case need be carried out peripheral blood autologous hematopoietic stem cell transplantation, and Plerixafor associating G-CSF can obviously improve the quantity of CD34+ cell in peripheral blood in patients, approximately can make 60% patient's peripheral blood CD34+ cell increase, guarantee the success of NHL and MM patient's autologous hematopoietic stem cell transplantation.
U.S. FDA is ratified its listing on December 15th, 2008, clinical study shows, this product can increase substantially patient's quantity of leucocyte and promote hemopoietic stem cell from marrow to blood flow, has synergy with granulocyte colony-stimulating factor (G-CSF); For the clinical experiment of multiple myeloma and hodgkin lymphoma patient stem cell transplantation.
About the synthetic of Plerixafor or its analogue, there are some bibliographical informations both at home and abroad, mainly contain J.Org.Chem.2003,68,6435-6436; J.Med Chem.1995,38 (2): 366-378; J.Synth Commun.1998,28:2903-2906; Tetrahedron, 1989,45 (1): 219-226; Chinese Journal of Pharmaceuticals 2007,38 (6); World patent WO9634860A1; WO9312096A1; U.S. Pat 5047527, US5606053, US5801281, US5064956, Chinese patent CN1466579A.
J.Med Chem.1995,38 (2): the preparation method that 366-378 relates to comprises the following steps: the trimethylbenzene naphthenic acid salt that 1) forms four nitrogen miscellaneous macrocyclic compound; 2) shielded four nitrogen miscellaneous macrocyclic compound is reacted as dibromo p-Xylol under as the existence of salt of wormwood in acetonitrile with organic dihalide at alkali; 3) use the newly target product of sodium amalgam, the vitriol oil or acetic acid/Hydrogen bromide mixture deprotection of preparation.
US 5047527 relates to the method for the ring-type tetramine of preparing monofunctional, and the method comprises: 1) make unprotected macrocylc compound react with Chromium hexacarbonyl, obtain four azepine hydride compounds of three protections; 2) free amine group of three protection compounds reacts to obtain the three tetraazacyclododecane hydride compounds of monofunctional of protecting with Organohalogen compounds; 3) carry out simple atmospheric oxidation, deprotection obtains target product.
J.Synth Commun.1998,28:2903-2906 has described a kind of synthetic method of improved Plerixafor intermediate, and the method adopts phosphorus protection, goes protection to obtain smoothly 1; 1 '-[Isosorbide-5-Nitrae-phenylene two (methylene radical)]-bis--Isosorbide-5-Nitrae; 8,11-tetraazacyclododecane tetradecane.
US 5606053 relates to one and prepares dimer 1,1 '-[Isosorbide-5-Nitrae-phenylene two (methylene radical)]-bis--Isosorbide-5-Nitrae, the method for 8,11-tetraazacyclododecane tetradecane.This compound preparation comprises: by tetramine, be 1) starting raw material, through toluene semi-annular jade pendant acidylate, obtain acyclic dimethylbenzene semi-annular jade pendant acyl intermediate and trimethylbenzene toluene semi-annular jade pendant acyl intermediate; 2) will after Fen Li with trimethylbenzene toluene semi-annular jade pendant acyl intermediate dimethylbenzene semi-annular jade pendant acyl intermediate, use dibromo xylene alkylation, then toluene semi-annular jade pendant acylations obtains the non-annularity dimer of mellitene semi-annular jade pendant acidylate; 3) separate the mellitene semi-annular jade pendant acyl group non-annularity dimer that obtains bridging and react with the ethylene glycol bisthioglycolate tosylate of three equivalents, cyclization; 4) by Hydrogen bromide and Glacial acetic acid deprotection, obtain target product.
US 5801281 relates to and prepares dimer 1,1 '-[Isosorbide-5-Nitrae-phenylene two (methylene radical)]-bis--Isosorbide-5-Nitrae, 8,11
The method of-tetraazacyclododecane tetradecane, comprising: 1) make non-annularity tetramine react with 3 equivalent Trifluoroacetic Acid Ethyl Esters; 2) with the dibromo xylene of 0.5 equivalent, the non-annularity tetramine alkylation of three protections is obtained to non-annularity dimer; 3) six trifluoroacetyl groups in compound are removed in hydrolysis; 4) compound toluene semi-annular jade pendant acidylate is obtained to bridging tetramine dimer; 5) spent glycol dimethylbenzene semi-annular jade pendant acid esters cyclisation; 6) with Hydrogen bromide and glacial acetic acid mixing acid deprotection, obtain target product.
US 5064956 discloses a kind of method of many azo-cycle compounds of preparing monoalkylation, the method relate to make unprotected macrocylc compound in proton inertia, relatively non-polar solvent, alkali-free exist condition under react with electrophilic reagent.In the document, do not mention the dimeric synthetic embodiment of similar plug Crane.
By synthetic route literature survey and Macro or mass analysis to disclosed Plerixafor, synthetic route mainly contains following four:
Route one, is with Isosorbide-5-Nitrae, and 8,11-tetraazacyclododecane tetradecane is raw material, and through N1, N4, N8 tri-protects, and with the bridging of Isosorbide-5-Nitrae-bis-(halogenated methyl) benzene, deprotection makes finished product.Reaction scheme is as follows, and wherein R is p-toluenesulfonyl, methylsulfonyl, and trifluoroacetyl group, tertbutyloxycarbonyl etc.:
Route two, is take two (2-aminopropyl) quadrol as raw material, after ring and reaction, with the bridging of Isosorbide-5-Nitrae-bis-(halogenated methyl) benzene, then obtains Plerixafor through deprotection.
Route three, with Isosorbide-5-Nitrae, 8,11-tetraazacyclododecane tetradecane is raw material, under anhydrous, oxygen free condition, after encircling interior protection, with the bridging of Isosorbide-5-Nitrae-bis-(halogenated methyl) benzene, then obtains Plerixafor through deprotection.Synthetic route chart is as follows, and wherein R is P, Ni etc.;
Route four; take methyl acrylate as starting raw material, first take quadrol as raw material through Michael addition, aminolysis, then obtain 1 with dimethyl malonate cyclization; 4; 8,11-, tetra-azepine-5,7; the 12-trioxy-ring tetradecane; through α, the bridging of α '-dibromo p-Xylol, obtains Plerixafor finally by deprotection.Reaction scheme figure is as follows:
There is following shortcoming in above route and existing synthetic method:
Route one, in intermediate building-up process, with existing technology, need to carry out column purification to each intermediate, and yield is low.
Route two, because interior protection stability is stronger, causes final step to be difficult to carry out deprotection reaction, and the production cycle is long, and yield is low, and the organic residue in finished product cannot reach in standard limit.
Route three is had relatively high expectations to anhydrous and oxygen-free, severe reaction conditions, and deprotection is not thorough, and intermediate needs column purification repeatedly, and yield is low, and through recrystallization repeatedly, finished product list is assorted to be difficult to be controlled at below 0.1%.
Route four needs anhydrous ethylenediamine and anhydrous THF, requires comparatively strictly in technique, and will use hazardous substance borine dimethyl sulphide, and second step yield is lower simultaneously only has 35% left and right.The not high shortcoming of selectivity of reaction, therefore neither most economical rational synthetic route.
We by above disclosed Plerixafor preparation method prepare Plerixafor single contaminant to be controlled at below 0.1% be very inaccessible, be difficult to meet the specification of quality of injection raw material, do not reach equally the correlation technique requirement of the quality approach technical director of European Union principle ICH, yield is low, cost is high, respectively walks the required quantity of solvent of intermediate column purification very large, consuming time longer, and eluting solvent toxicity is larger, is unfavorable for suitability for industrialized production.
Summary of the invention
In order to solve the technical barrier existing in above-mentioned prior art, the present invention is from another angle, by special method of purification, obtain the reaction intermediate that purity is higher, to avoid the side reaction of follow-up complexity, adopt the refining also method of segmentation crystallization removal of impurities of mixed solvent, prepare highly purified Plerixafor.
The invention provides a kind of method of preparing Plerixafor, comprise the following steps:
(1) prepare Isosorbide-5-Nitrae, 8-tri-(p-toluenesulfonyl)-1,4,8,11-tetraazacyclododecane tetradecane: by raw material 1,4,8,11-tetraazacyclododecane tetradecane is suspended in methylene dichloride, under acid binding agent effect, at 10～30 ℃ of temperature, react 3～8h with Tosyl chloride, filter, collect filtrate and be concentrated into the dry resistates that obtains; By a kind of C of described resistates
1~ C
3the mixed solvent of alkyl alcohol and a kind of aprotic solvent is refining, and segmentation crystallization obtains the Isosorbide-5-Nitrae that purity is greater than 95%, 8-tri-(p-toluenesulfonyl)-Isosorbide-5-Nitrae, 8,11-tetraazacyclododecane tetradecane;
(2) prepare 1,1 '-[Isosorbide-5-Nitrae-(phenylene dimethylene)]-bis--[4,8,11-tri-(p-toluenesulfonyl)]-Isosorbide-5-Nitrae, 8,11-tetraazacyclododecane tetradecane: by (1) gained Isosorbide-5-Nitrae, 8-tri-(p-toluenesulfonyl)-Isosorbide-5-Nitrae, 8,11-tetraazacyclododecane tetradecane, α, α '-dibromo p-Xylol is placed in anhydrous acetonitrile, adds acid binding agent, back flow reaction 5～24 hours under nitrogen protection; After reaction, be cooled to room temperature, then reacted mixture filtered, collect filter cake, after mixed solvent is refining, obtain 1,1 '-[Isosorbide-5-Nitrae-(phenylene dimethylene)]-bis--[4,8,11-tri-(p-toluenesulfonyl)]-1,4,8,11-tetraazacyclododecane tetradecane;
(3) synthetic Plerixafor: by (2) gained 1,1 '-[Isosorbide-5-Nitrae-(phenylene dimethylene)]-bis--[4,8,11-tri-(p-toluenesulfonyl)]-Isosorbide-5-Nitrae, 8,11-tetraazacyclododecane tetradecane joins in mixed acid solution, stirring and dissolving, is warming up to back flow reaction 10～24 hours, cooling, filter, collect filter cake; Described filter cake is dissolved in to purified water, with potassium hydroxide solution or sodium hydroxide solution adjusting pH to 12, filters, filtrate extracts with halogenated solvent, gets organic layer anhydrous sodium sulfate drying, then filters, and gets the concentrated Plerixafor crude product that to obtain of filtrate decompression;
(4) purifying Plerixafor: Plerixafor crude product is placed in to solvent and dissolves, being warming up to refluxes dissolves, and filters, and drips crystallization solvent, in 40～45 ℃ of crystallization 30min, to filter, filtrate is cooled to 20～25 ℃ of crystallizatioies 1 hour again, in 0～5 ℃ of crystallization 3 hours, filter, filtration cakes torrefaction obtains Plerixafor.
Described in step (1), acid binding agent is DIPEA.
Described in step (1), treating process comprises two temperature stages, in subordinate phase, adds and C
1~ C
3the ether of the weight such as alkyl alcohol is to promote crystallization; Described C
1~ C
3alkyl alcohol is methyl alcohol, ethanol, n-propyl alcohol and Virahol; Described non-protonic solvent is in methylene dichloride, acetone and toluene; Described C
1~ C
3alkyl alcohol and raw material Isosorbide-5-Nitrae, the weight ratio of 8,11-tetraazacyclododecane tetradecane is 2～10:1; Described aprotic solvent and alkyl alcohol weight ratio are 1:2～3.Described C
1~ C
3alkyl alcohol is methyl alcohol; Non-protonic solvent is toluene; Two temperature stages of segmentation crystallization are 40～45 ℃ of crystallization 30min, 0～5 ℃ of crystallization 3h; The ether that described segmentation crystallization subordinate phase adds is methyl tertiary butyl ether.
Acid binding agent described in step (2) is the mixture of a kind of or arbitrary combination in sodium carbonate, Quilonum Retard, salt of wormwood, cesium carbonate, Strontium carbonate powder; Refining mixed solvent is the mixed solvent of anhydrous methanol, ethyl acetate, methylene dichloride, and the volume ratio of described anhydrous methanol, ethyl acetate, methylene dichloride is 1:2～8:1.The preferred sodium carbonate of described acid binding agent; The preferred 1:3:1 of volume ratio of anhydrous methanol, ethyl acetate and methylene dichloride in refining mixed solvent.
Nitration mixture described in step (3) is the mixing solutions of glacial acetic acid and hydrochloric acid; The halogenated solvent adopting in described extraction is one or both mixture of methylene dichloride, trichloromethane.The preferred methylene dichloride of described halogenated solvent.
Described in step (4), the dissolution solvent of Plerixafor crude product is tetrahydrofuran (THF); Described crystallization solvent is the mixture of a kind of or arbitrary combination in sherwood oil, normal hexane, normal heptane, hexanaphthene, ether, propyl ether, isopropyl ether.Described crystallization solvent is preferably normal hexane.The add-on of dissolution solvent tetrahydrofuran (THF) is 8～10 times of weight of crude product weight, 1～3 times of weight that the add-on of crystallization solvent is dissolution solvent.
The present invention is through a large amount of experimental studies, study one by one the relation of each intermediate and finished product purity and yield, (chemistry is by name: 1 for final definite Plerixafor synthetic intermediate, 4,8-tri-(p-toluenesulfonyl)-1, the purity of 4,8,11-tetraazacyclododecane tetradecane will directly affect purity and the yield of finished product; Intermediate Isosorbide-5-Nitrae, 8-tri-(p-toluenesulfonyl)-Isosorbide-5-Nitrae, it is particularly crucial that the control of purity of 8,11-tetraazacyclododecane tetradecane seems, if it is very low to control the bad synthesis yield that will cause, and affect end product quality also cannot purifying.The present invention avoids the troublesome operation that product need be repeatedly refining, and makes to reach more than 99.5% through the finished product purity of primary purification Plerixafor, and the production technology exploitation that single contaminant is controlled at below 0.1% seems particularly important.
The detection method of Plerixafor purity of the present invention is HPLC method;
Take octadecylsilane chemically bonded silica as weighting agent; Take 0.1mol/L sodium heptanesulfonate-methyl alcohol (9: 1) as mobile phase A; Take 0.1mol/L sodium heptanesulfonate-methyl alcohol (3: 7) as Mobile phase B; Column temperature: 40.0 ℃; Flow velocity: 1.2ml/ minute; Sampling volume: 20 μ l; Detection wavelength is 230nm, and number of theoretical plate calculates and is not less than 2500 by Plerixafor peak.
Gradient Features:
| Time (minute) | %A | %B | Curve |
| 0 | 95 | 5 | Initially |
| 35 | 60 | 40 | Linear |
| 55 | 60 | 40 | Linear |
| 62 | 0 | 100 | Keep |
Dissolvent residual detection method of the present invention is GC method:
According to vapor-phase chromatography (two appendix V E of Chinese Pharmacopoeia version in 2010), measure.Adopt OV-101 capillary chromatographic column, specification: 30m × 0.53mm × 1.0 μ m, column temperature: 35 ℃ keep, after 7 minutes, rising to 150 ℃ with 30 ℃ of per minutes, keep 3 minutes.Flame ionization ditector temperature is 200 ℃.Measure respectively the each 1 μ l of reference substance solution and need testing solution, inject gas chromatograph, records color atlas.
Adopt technical scheme of the present invention, can have following beneficial effect:
1) the Plerixafor bulk drug that adopts method of the present invention to prepare, product purity is very high, reach more than 99.5%, single contaminant is less than 0.1%, quality product can meet the requirement of injection raw material, reached equally the correlation technique requirement of the quality approach technical director of European Union principle ICH, for preparation research provides up-to-standard starting material;
2) preparation method's technological process of the present invention is easy, and cost is low, and technique is easy to suitability for industrialized production; The preparation impurity that adopts this raw material to make is few, and organic residue meets drug quality regulation.Good effect, untoward reaction is low, for patient brings maximum benefit.
Embodiment
embodiment 1: the preparation (reference example 1) of Plerixafor
Reference literature Chinese Journal of Pharmaceuticals 2007,38 (6) is prepared Plerixafor, or prepares with reference to following methods:
By 1,4,8,11-tetraazacyclododecane tetradecane (5g, 25mmo1), triethylamine (18m1) and methylene dichloride (150m1) are put in reaction flask, room temperature drips Tosyl chloride (8.1g, methylene dichloride (300m1) solution 51mmo1), drips complete stirred overnight at room temperature, adds water (40m1), stratification, organic phase is spent the night with anhydrous sodium sulfate drying, filters, and filtrate decompression is steamed except methylene dichloride, residuum recrystallizing methanol, obtains 6.5g.Mother liquor removes solvent under reduced pressure; in residue oily matter, add methylene dichloride (100m1) and triethylamine (10m1); drip Tosyl chloride (2.0g; methylene dichloride (50m1) solution 10mmo1); room temperature reaction 2h; remove methylene dichloride under reduced pressure; residuum recrystallizing methanol, the solid obtaining merges with the solid obtaining above, altogether 1; 4; 8-tri-(p-toluenesulfonyl)-Isosorbide-5-Nitrae, 8; 11-tetraazacyclododecane tetradecane (5.7g, 40.7%).
By above-mentioned gained sample (5.5g, 8.3mmo1), α, α '-dibromo p-Xylol, Anhydrous potassium carbonate (3.4g, 25mmo1) and anhydrous acetonitrile (80m1) are put in 150ml eggplant-shape bottle, reflux 20h under vigorous stirring.Cooled and filtered, filter cake washed with dichloromethane, filtrate and washing lotion merge, and remove solvent under reduced pressure, and residuum drying under reduced pressure, obtains white solid (4.9g, 78.2%).
By above-mentioned intermediate (4.0g, 0.28mmo1), 48% Hydrogen bromide (24m1) and glacial acetic acid (36m1) put in 100ml reaction flask, stirs lower reflux 48h, has micro-yellow solid to separate out, be cooled to room temperature, filter, filter cake is used glacial acetic acid (100ml × 3) successively, anhydrous diethyl ether (60ml × 3) washing, drying under reduced pressure at 40 ℃, use 95% ethyl alcohol recrystallization, obtain Plerixafor (0.65g, 78%).Purity 99.1%, maximum single assorted 0.34%.
embodiment 2: the preparation (reference example) of Plerixafor
Reference literature CN1466579 prepares Plerixafor, or prepares with reference to following methods:
By Isosorbide-5-Nitrae, 8,11-tetraazacyclododecane tetradecane (7.5g, 37.6mmol) is dissolved in methyl alcohol (30ml), adds triethylamine (5.2ml), after stirring 5min, slowly adds Trifluoroacetic Acid Ethyl Ester (18ml, 150.3mol), room temperature reaction 5h under nitrogen protection.At 40 ℃, concentrating under reduced pressure is removed methyl alcohol, and column purification, obtains white solid (12.7g, 68.9%).
By Isosorbide-5-Nitrae, 8-tri-(trifluoroacetyl group) Isosorbide-5-Nitrae, 8,11-, the tetra-azepine tetradecanes (7.4g, 15.14mmol), anhydrous acetonitrile (40ml) add in reaction flask, and stirring at room is dissolved.In reaction solution, add salt of wormwood (3.2g, 22.7mmol), potassiumiodide (0.127g, 0.76mmol) and xylene dichloride (1.33g, 7.56mmol), under nitrogen protection, be added to backflow, react 24 hours.Be cooled to room temperature, filter, acetonitrile washing, concentrating under reduced pressure filtrate obtains faint yellow solid.Solid ethanol: purified water (4:1) recrystallization obtains white solid (6.8g, 82.6%).
1,1 '-[Isosorbide-5-Nitrae-(phenylene dimethylene)]-bis--[4; 8,11-tri-(trifluoroacetyl group)]-Isosorbide-5-Nitrae; 8; 11-tetraazacyclododecane tetradecane (6.6g, 6.1mmol) is dissolved in methyl alcohol 15ml, adds salt of wormwood (2.6g; 18.2mmol); be heated to back flow reaction 3 hours, toluene 60ml is added in cooling reactant, azeotropic is removed methyl alcohol.Remove by filter inorganic salt, filtrate is concentrated obtains off-white color solid (1.54g, 50.2%), purity 98.6%, maximum single assorted 0.17%.
embodiment 3: the preparation of Plerixafor
By raw material 1, 4, 8, 11-tetraazacyclododecane tetradecane (5g, 25mmol) be suspended in methylene dichloride (50g), add N, N-diisopropylethylamine (5ml), drip Tosyl chloride (9.5g, solution 50mmol) being made into methylene dichloride (50g), drip to finish at 20～30 ℃ of temperature and react 6h, filter, collecting filtrate is concentrated into dry, in resistates, add ethanol (40g) and acetone (20g), be heated to reflux, filter, filtrate is cooled to 45 ℃ of crystallization 30min, remove by filter the impurity of a little overprotection, filtrate adds methyl tertiary butyl ether (40g), under stirring, be quickly cooled to 0～5 ℃ of crystallization 3h to obtain 1, 4, 8-tri-(p-toluenesulfonyl)-1, 4, 8, 11-tetraazacyclododecane tetradecane (8.7g, 56.1%), purity 96.2%.
By Isosorbide-5-Nitrae, 8-tri-(p-toluenesulfonyl)-1; 4; 8,11-tetraazacyclododecane tetradecane (5.5g, 8.3mmol); α; α '-dibromo p-Xylol (1.1g, 4.2mmol) is placed in anhydrous acetonitrile (40g), adds Quilonum Retard (4.9g; 66.3mmol), back flow reaction 24 hours under nitrogen protection.Be cooled to room temperature and filter, collect filter cake, add anhydrous methanol (12ml), ethyl acetate (96ml), methylene dichloride (12ml) thermosol is refining, and cooling crystallization filters, and drying under reduced pressure obtains off-white color solid (10.3g, 86.8%), purity 96.4%.
Above-mentioned gained intermediate (10g, 7mmol) is joined in glacial acetic acid (80ml) and concentrated hydrochloric acid (80ml) mixing solutions, be stirred to dissolving, be warming up to back flow reaction 15 hours, cooling, filter, collect filter cake.Filter cake is dissolved in purified water (50ml), by potassium hydroxide solution adjusting pH value to 12, filters, filtrate extracts with methylene dichloride (100ml × 3), and organic layer anhydrous sodium sulfate drying filters, concentrating under reduced pressure obtains Plerixafor crude product (2.7g, 77.1%), purity 98.7%.
Plerixafor crude product (2.3g, 4.6mmol) is placed in to tetrahydrofuran (THF) (18.4g), and being warming up to refluxes dissolves, filter, drip sherwood oil (37g), with 40～45 ℃ of crystallization 30min, filter a little solid, filtrate fast cooling to 20～25 ℃ crystallization 1 hour, then in 0～5 ℃ of crystallization 3 hours, filter, be dried to obtain Plerixafor finished product (2.1g, 91.3%), purity 99.91%, maximum single assorted 0.07%.
embodiment 4: the preparation of Plerixafor
By raw material 1, 4, 8, 11-tetraazacyclododecane tetradecane (5g, 25mmol) be suspended in methylene dichloride (25g), add N, N-diisopropylethylamine (7.5ml), drip Tosyl chloride (11.9g, solution 62.5mmol) being made into methylene dichloride (25g), at 10～20 ℃ of temperature, react 8h, filter, collecting filtrate is concentrated into dry, in resistates, add n-propyl alcohol (30g), methylene dichloride (10g) is heated to reflux, filter, filtrate is cooled to 40 ℃ of crystallization 30min, filter, filtrate adds methyl tertiary butyl ether (30g), under stirring, be quickly cooled to 0～5 ℃ of crystallization 3h, filter, dry 1, 4, 8-tri-(p-toluenesulfonyl)-1, 4, 8, 11-tetraazacyclododecane tetradecane (9.4g, 60.6%), purity 95.6%.
By Isosorbide-5-Nitrae, 8-tri-(p-toluenesulfonyl)-1; 4,8,11-tetraazacyclododecane tetradecane (7.7g; 11.6mmol); α, α '-dibromo p-Xylol (1.52g, 5.74mmol) is placed in anhydrous acetonitrile (150ml); add cesium carbonate (15.3g; 47.0mmol), Strontium carbonate powder (7.0g, 47.4mmol), back flow reaction 15 hours under nitrogen protection.Be cooled to room temperature and filter, collect filter cake, add anhydrous methanol (10ml), ethyl acetate (20ml), methylene dichloride (10ml) thermosol is refining, and cooling crystallization filters, and drying under reduced pressure obtains off-white color solid (13.9g, 83.7%), purity 97.2%.
Above-mentioned gained intermediate (5g, 3.5mmol) is joined in glacial acetic acid (50ml) and concentrated hydrochloric acid (50ml) mixing solutions and is stirred to dissolving, be warming up to back flow reaction 10 hours, cooling, filter, collect filter cake.Filter cake is dissolved in purified water (30ml), by potassium hydroxide solution adjusting pH value to 12, filters, and filtrate extracts with trichloromethane (80ml × 3), and organic layer anhydrous sodium sulfate drying filters, and concentrating under reduced pressure obtains Plerixafor crude product (1.4g, 79.5%), purity 98.2%.
Plerixafor crude product 1.2g is placed in to tetrahydrofuran (THF) (10.8g), and being warming up to refluxes dissolves, and filters, drip ether/isopropyl ether (1:1, v/v) (10.8g), with 40～45 ℃ of crystallization 30min, filter a little solid, filtrate fast cooling to 20～25 ℃ crystallization 1 hour, then in 0～5 ℃ of crystallization 3 hours, filter, 45 ℃ of drying under reduced pressure obtain Plerixafor finished product (1.04g, 86.7%), purity 99.93%, maximum single assorted 0.05%.
embodiment 5: the preparation of Plerixafor
By raw material 1, 4, 8, 11-tetraazacyclododecane tetradecane (5g, 25mmol) be suspended in methylene dichloride (50g), add N, N-diisopropylethylamine (7.5ml), drip Tosyl chloride (10.8g, solution 56.5mmol) being made into methylene dichloride (50g), at 25～30 ℃ of temperature, react 3h, filter, collecting filtrate is concentrated into dry, in resistates, add Virahol (30g), toluene (10g) is heated to reflux, filter, filtrate is cooled to 40 ℃ of crystallization 30min, remove by filter the impurity of a little overprotection, filtrate adds methyl tertiary butyl ether (30g), under stirring, be quickly cooled to 0～5 ℃ of crystallization 3h, filter, dry 1, 4, 8-tri-(p-toluenesulfonyl)-1, 4, 8, 11-tetraazacyclododecane tetradecane (9.6g, 61.9%), purity 97.2%.
By 1; 4,8-tri-(p-toluenesulfonyl)-Isosorbide-5-Nitrae; 8; 11-tetraazacyclododecane tetradecane (9g, 13.6mmol) α, α '-dibromo p-Xylol (1.81g; 6.8mmol) be placed in anhydrous acetonitrile (90ml); add sodium carbonate (11.5g, 108.5mmol), back flow reaction 5 hours under nitrogen protection.Be cooled to room temperature and filter, collect filter cake, add anhydrous methanol (10ml), ethyl acetate (30ml), methylene dichloride (10ml) thermosol is refining, and cooling crystallization filters, and drying under reduced pressure obtains off-white color solid (16.1g, 83%), purity 97.5%.
Above-mentioned gained intermediate (5g, 3.5mmol) is joined in glacial acetic acid (25ml) and concentrated hydrochloric acid (25ml) mixing solutions and is stirred to dissolving, be warming up to back flow reaction 24 hours, cooling, filter, collect filter cake.Filter cake is dissolved in purified water (20ml), by sodium hydroxide solution adjusting pH value to 12, filters, filtrate extracts with trichloromethane (50ml × 3), and organic layer anhydrous sodium sulfate drying filters, concentrating under reduced pressure obtains Plerixafor crude product (1.4g, 79.5%), purity 98.6%.
Plerixafor crude product (1.4g) is placed in to tetrahydrofuran (THF) (14g), and being warming up to refluxes dissolves, and filters, drip normal heptane (42g), with 40～45 ℃ of crystallization 30min, filter a little solid, filtrate fast cooling to 20～25 ℃ crystallization 1 hour, again in 0～5 ℃ of crystallization 3 hours, filter, 45 ℃ of drying under reduced pressure obtain Plerixafor finished product (1.2g, 85.7%), purity 99.94%, maximum single assorted 0.04%.
embodiment 6: the preparation of Plerixafor
By raw material 1, 4, 8, 11-tetraazacyclododecane tetradecane (5g, 25mmol) be suspended in methylene dichloride (50g), add N, N-diisopropylethylamine (7.5ml), drip Tosyl chloride (10.8g, solution 56.5mmol) being made into methylene dichloride (50g), at 25～30 ℃ of temperature, react 3h, filter, collecting filtrate is concentrated into dry, in resistates, add methyl alcohol (30g), toluene (10g) is heated to reflux, filter, filtrate is cooled to 40 ℃ of crystallization 30min, remove by filter the impurity of a little overprotection, filtrate adds methyl tertiary butyl ether (30g), under stirring, be quickly cooled to 0～5 ℃ of crystallization 3h, filter, dry 1, 4, 8-tri-(p-toluenesulfonyl)-1, 4, 8, 11-tetraazacyclododecane tetradecane (9.6g, 61.9%), purity 97.2%.
By 1; 4,8-tri-(p-toluenesulfonyl)-Isosorbide-5-Nitrae; 8; 11-tetraazacyclododecane tetradecane (9g, 13.6mmol) α, α '-dibromo p-Xylol (1.81g; 6.8mmol) be placed in anhydrous acetonitrile (90ml); add salt of wormwood (15.0g, 108.5mmol), back flow reaction 5 hours under nitrogen protection.Be cooled to room temperature and filter, collect filter cake, add anhydrous methanol (10ml), ethyl acetate (30ml), methylene dichloride (10ml) thermosol is refining, and cooling crystallization filters, and drying under reduced pressure obtains off-white color solid (16.1g, 83%), purity 97.5%.
Above-mentioned gained intermediate (5g, 3.5mmol) is joined in glacial acetic acid (25ml) and concentrated hydrochloric acid (25ml) mixing solutions and is stirred to dissolving, be warming up to back flow reaction 24 hours, cooling, filter, collect filter cake.Filter cake is dissolved in purified water (20ml), by sodium hydroxide solution adjusting pH value to 12, filters, filtrate extracts with methylene dichloride (50ml × 3), and organic layer anhydrous sodium sulfate drying filters, concentrating under reduced pressure obtains Plerixafor crude product (1.4g, 79.5%), purity 98.6%.
Plerixafor crude product (1.4g) is placed in to tetrahydrofuran (THF) (14g), and being warming up to refluxes dissolves, and filters, drip normal hexane (42g), with 40～45 ℃ of crystallization 30min, filter a little solid, filtrate fast cooling to 20～25 ℃ crystallization 1 hour, again in 0～5 ℃ of crystallization 3 hours, filter, 45 ℃ of drying under reduced pressure obtain Plerixafor finished product (1.2g, 85.7%), purity 99.93%, maximum single assorted 0.04%.
Embodiment 1 and 2 prepares the method for Plerixafor for prior art, and the purity of its Plerixafor preparing is far below the inventive method, and maximum single assorted amount is also much larger than the present invention.The security of Plerixafor prepared by the present invention is higher.
Claims (6)
1. a method of preparing Plerixafor, comprises the following steps:
(1) prepare Isosorbide-5-Nitrae, 8-tri-(p-toluenesulfonyl)-1,4,8,11-tetraazacyclododecane tetradecane: by raw material 1,4,8,11-tetraazacyclododecane tetradecane is suspended in methylene dichloride, under acid binding agent effect, at 10～30 ℃ of temperature, react 3～8h with Tosyl chloride, filter, collect filtrate and be concentrated into the dry resistates that obtains; By a kind of C of described resistates
1~ C
3the mixed solvent of alkyl alcohol and a kind of aprotic solvent is refining, and segmentation crystallization obtains the Isosorbide-5-Nitrae that purity is greater than 95%, 8-tri-(p-toluenesulfonyl)-Isosorbide-5-Nitrae, 8,11-tetraazacyclododecane tetradecane;
(2) prepare 1,1 '-[Isosorbide-5-Nitrae-(phenylene dimethylene)]-bis--[4,8,11-tri-(p-toluenesulfonyl)]-Isosorbide-5-Nitrae, 8,11-tetraazacyclododecane tetradecane: by (1) gained Isosorbide-5-Nitrae, 8-tri-(p-toluenesulfonyl)-Isosorbide-5-Nitrae, 8,11-tetraazacyclododecane tetradecane, α, α '-dibromo p-Xylol is placed in anhydrous acetonitrile, adds acid binding agent, back flow reaction 5～24 hours under nitrogen protection; After reaction, be cooled to room temperature, then reacted mixture filtered, collect filter cake, after mixed solvent is refining, obtain 1,1 '-[Isosorbide-5-Nitrae-(phenylene dimethylene)]-bis--[4,8,11-tri-(p-toluenesulfonyl)]-1,4,8,11-tetraazacyclododecane tetradecane;
(3) synthetic Plerixafor: by (2) gained 1,1 '-[Isosorbide-5-Nitrae-(phenylene dimethylene)]-bis--[4,8,11-tri-(p-toluenesulfonyl)]-Isosorbide-5-Nitrae, 8,11-tetraazacyclododecane tetradecane joins in mixed acid solution, stirring and dissolving, is warming up to back flow reaction 10～24 hours, cooling, filter, collect filter cake; Described filter cake is dissolved in to purified water, with potassium hydroxide solution or sodium hydroxide solution adjusting pH to 12, filters, filtrate extracts with halogenated solvent, gets organic layer anhydrous sodium sulfate drying, then filters, and gets the concentrated Plerixafor crude product that to obtain of filtrate decompression;
(4) purifying Plerixafor: Plerixafor crude product is placed in to solvent and dissolves, being warming up to refluxes dissolves, and filters, and drips crystallization solvent, in 40～45 ℃ of crystallization 30min, to filter, filtrate is cooled to 20～25 ℃ of crystallizatioies 1 hour again, in 0～5 ℃ of crystallization 3 hours, filter, filtration cakes torrefaction obtains Plerixafor;
Described in described step (1), acid binding agent is DIPEA;
Described in described step (1), treating process comprises two temperature stages, in subordinate phase, adds and C
1~ C
3the ether of the weight such as alkyl alcohol is to promote crystallization; Described C
1~ C
3alkyl alcohol is methyl alcohol, ethanol, n-propyl alcohol and Virahol; Described non-protonic solvent is methylene dichloride, acetone and toluene; Described C
1~ C
3alkyl alcohol and raw material Isosorbide-5-Nitrae, the weight ratio of 8,11-tetraazacyclododecane tetradecane is 2～10:1; Described aprotic solvent and alkyl alcohol weight ratio are 1:2～3;
Acid binding agent described in described step (2) is the mixture of a kind of or arbitrary combination in sodium carbonate, Quilonum Retard, salt of wormwood, cesium carbonate, Strontium carbonate powder; Refining mixed solvent is the mixed solvent of anhydrous methanol, ethyl acetate, methylene dichloride, and the volume ratio of described anhydrous methanol, ethyl acetate, methylene dichloride is 1:2～8:1;
Nitration mixture described in described step (3) is the mixing solutions of glacial acetic acid and hydrochloric acid; The halogenated solvent adopting in described extraction is one or both mixture of methylene dichloride, trichloromethane;
Described in described step (4), the dissolution solvent of Plerixafor crude product is tetrahydrofuran (THF); Described crystallization solvent is the mixture of a kind of or arbitrary combination in sherwood oil, normal hexane, normal heptane, hexanaphthene, ether, propyl ether, isopropyl ether.
2. prepare according to claim 1 the method for Plerixafor, it is characterized in that C described in step (1)
1~ C
3alkyl alcohol is methyl alcohol; Non-protonic solvent is toluene; Two temperature stages of segmentation crystallization are 40～45 ℃ of crystallization 30min, 0～5 ℃ of crystallization 3h; The ether that described segmentation crystallization subordinate phase adds is methyl tertiary butyl ether.
3. prepare according to claim 1 the method for Plerixafor, it is characterized in that described in step (2), acid binding agent is sodium carbonate; The volume ratio of anhydrous methanol, ethyl acetate and methylene dichloride in refining mixed solvent is 1:3:1.
4. prepare according to claim 1 the method for Plerixafor, it is characterized in that described in step (2), halogenated solvent is methylene dichloride.
5. prepare according to claim 1 the method for Plerixafor, it is characterized in that described in step (4), crystallization solvent is normal hexane.
6. prepare according to claim 1 the method for Plerixafor, it is characterized in that the add-on of dissolution solvent tetrahydrofuran (THF) in step (4) is 8～10 times of weight of crude product weight, 1～3 times of weight that the add-on of crystallization solvent is dissolution solvent.
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| CN103232403B (en) * | 2013-05-09 | 2016-04-27 | 浙江凯普化工有限公司 | A kind of preparation method of nitrogen heterocyclic |
| CN104211652B (en) * | 2014-08-27 | 2016-09-07 | 吉林大学 | A kind of method preparing Plerixafor |
| CN112903861B (en) * | 2021-01-26 | 2022-11-15 | 山东省药学科学院 | Method for detecting residual solvent in dextral rabeprazole sodium bulk drug |
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| 苏靖、刘瑶、郑志兵等.Plerixafor的合成.《中国医药工业杂志》.2007,第38卷(第6期),第398-400页. |
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