CN105418603A - Method for preparing high-purity palbociclib and reaction intermediate of palbociclib - Google Patents
Method for preparing high-purity palbociclib and reaction intermediate of palbociclib Download PDFInfo
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The invention relates to a method for preparing compound palbociclib (shown as the formula I). A compound D (shown as the formula II) serves as a raw material, and a compound E (shown as the formula III) is obtained through a rearrangement reaction of alkenyl ether; then the compound E is subjected to t-butyloxycarboryl protection group removal under the acidic condition, and target product palbociclib is obtained; an R group in a compound D is selected from any one of a C1-C6 alkyl group, a C1-C6 halogenate alkyl group, C1-C6 hydroxyalkyl and a C1-C6 naphthenic base. The process procedure and operation steps are easy and convenient, prepared palbociclib is high in purity, and good popularization prospects are achieved.
Description
Technical field
The invention belongs to medicinal chemistry art, the present invention relates to the preparation method of profit cloth of a kind of Pabuk former times, be specifically related to a kind ofly prepare high purity Pabuk former times profit cloth and the method for reaction intermediate thereof.
Background technology
Mammary cancer is not a single disease, and mammary cancer is divided into 4 types by the result that immunohistochemical methods detects ER, PR, HER2 and Ki67.But it is regardless of which kind of type, in fact all relevant with the imbalance of cell cycle.With cell cycle closely-related Cyclin dependent kinase 4/6 (cyclin-dependentkinase4/6, CDK4/6) inhibitor, serine/threonine kinases can be suppressed to be combined with cyclin D, and blocks cellular was changed to the S phase by the G1 phase.CDK4/6 inhibitor is antitumor as small molecules targeted drug, and advantage is: Selective depression CDK4/6, does not show the cytotoxicity of " general-CDK inhibitor ", as bone marrow depression and enteron aisle reaction; Because the cyclin D horizontal compared with normal cell of tumour cell is high, and increase the susceptibility of tumour cell to medicine, and then increase the targeting of medicine.
Pabuk former times profit cloth (Palbociclib); chemical name: 6-ethanoyl-8-cyclopentyl-5-methyl-2-(5-(piperazine-1-base) pyridine-2-base is amino) pyridine [2,3-d] pyrimidine 7 (8H)-one (such as formula I Suo Shi):
Its structure belongs to Pyridopyrimidine class, is the selective depressant of CDK4/6, IC
50(concentration corresponding when apoptotic cell and the ratio of whole cell count equal 50%) is respectively 11 and 15nmol/L, and the IC to CDK2, CDK1, CDK5
50be greater than 10 μm of ol/L.
This medicine is developed by Pfizer, be in February, 2015 by the CDK4/6 inhibitor of the first approval of U.S. FDA, for late period or the transitivity ER of menopausal women
+/ HER
2-the first-line treatment of mammary cancer; Be in the clinical trial before listing to comprise: high-risk breast carcinoma of early stage (III phase is clinical), liver cancer (II phase is clinical), epithelial ovarian cancer (II phase is clinical), leukemia (I b/ II a phase is clinical) nonsmall-cell lung cancer (II/III phase is clinical), multiple myeloma (I/II phase is clinical), colorectal cancer liver cancer (I phase is clinical), liposarcoma (II phase is clinical), melanoma (I/II phase is clinical), lymphoma mantle cell (I phase is clinical), solid tumor (II phase is clinical).
In February, 2015 goes on the market in the U.S. first, trade name is handkerchief pool former times cloth, listing formulation is capsule, has three specifications, is respectively 125mg, 100mg, 75mg, Pabuk former times profit cloth (Palbociclib) is a kind of breakthrough, oral, targeting CDK4/6 specific inhibitor, can Selective depression cell cycle protein dependent kinase 4 and 6 (CDK4/6), recover cell cycle control, block tumor cell proliferation.Clinical in previously not accepting systematic treating to control the postmenopausal women estrogen receptor positive (ER of the state of an illness in late period
+), human epidermal growth factor receptor 2's feminine gender (HER
2-) treatment of Locally Advanced or metastatic breast cancer.
According to document [1] WO2008032157A2, [2] WO2003062236A1, [3] WO2001070741A1, [4] MarkBarvian, DianeH.Boschelli, Jennifercossrow, etal, Pyrido [2, 3-d] pyrimidin-7-oneinhibitorsofCyclin-Dependentkinases [J] JMedChem, 2000, 43, pp4606-4616, [5] WO1998033798A2, [6] WO2005005426A1, [7] CN104447743A (is called for short document [1] below respectively, [2], [3], [4], [5], [6], [7]) several preparation methods of disclosed Pabuk former times profit cloth (Palbociclib), be summed up to mainly contain and mainly contain following two synthetic routes below, now respectively following two routes are set forth and are analyzed:
Route one: document
[1], [2], [3], [4], [5], [6]disclosed the first prepare the method for Pabuk former times profit cloth (Palbociclib), its synthesis strategy adopts compd A (Kui Linpyrimido quinoline pyridine ring fragment) and compd B (pyridine joins piperazine fragment) first condensation to prepare Compound C, then uses Pd catalyzer/Phosphine ligands and vinyl ether or its analogue to experience the linked reactions such as Heckreaction and Stillereaction and prepare Compound D.Final compound D obtains target molecule Pabuk former times profit cloth (Palbociclib) through using excessive strong acid to carry out deprotection and completing rearrangement reaction.Synthetic route following (Pabuk former times sharp cloth synthetic route one):
The present inventor prepares in the process of Pabuk former times profit cloth (Palbociclib) in overlapping route one embodiment, find to adopt the technical scheme of route one to be more difficult in preparation or acquisition high purity Pabuk former times profit cloth (Palbociclib), this mainly there is following shortcoming in route, one is use Pd catalyzer/Phosphine ligands and vinyl ether or its analogue to experience the linked reactions such as Heckreaction and Stillereaction to prepare in the process of Compound D, because temperature of reaction is higher, the time is longer.And employ Pd catalyzer/Phosphine ligands.First be that reaction easily produces some impurity similar to Compound D structure or polarity (solubleness) (such as impurity E, E1, E2, E3, in table one).These impurity are all with blocking group or do not complete rearrangement; bring in next step reaction process; deprotection or rearrangement reaction can be there is; generate again cloth (Palbociclib) structure sharp with target molecule Pabuk former times or the similar impurity (such as impurity F 1, F2, F3, in table one) of polarity (solubleness).Due to the singularity of bulk drug Pabuk former times profit cloth (Palbociclib) molecular structure, cause its solubleness in the middle of majority of organic solvent very low (remarks: under normal temperature, in testing laboratory or suitability for industrialized production, common organic solvents is about except 3mg/mL except methylene dichloride solubleness, other solvent ratio are as methyl alcohol, ethanol, acetone, acetonitrile, tetrahydrofuran (THF), ethyl acetate, propyl carbinol, N, dinethylformamide, even the solubleness of dimethyl sulfoxide (DMSO) all≤1mg/mL.Be between 90-110 DEG C in temperature, Pabuk former times profit cloth (Palbociclib) removes at phenylmethylether, in phenylmethylether/propyl carbinol (3:2V/V) outside solubleness >=25mg/mL, at other such as propyl carbinol, DMF, dimethyl sulfoxide (DMSO), solubleness in the high boiling solvents such as butylacetate is all less than 25mg/mL), be an insoluble drug.Due to each impurity structure or polarity (solubleness) close with product, cause purifying Pabuk former times profit cloth (Palbociclib) very difficult, extremely difficult acquisition meets medicinal requirements, highly purified product; Two is prepare in Pabuk former times profit cloth (Palbociclib) intermediate (Compound D) process, and because temperature of reaction is higher, the time is longer.And employ Pd catalyzer/Phosphine ligands.Produce the content higher (accounting for about 5-15%) of impurity E 1.Because impurity E 1 is at high temperature, the rearrangement product produced under long-time and catalyzer complex reaction system, this impurity is more special, brings next step experience deprotection reaction into, can be converted into product.Therefore, as carried out recrystallization purifying to Compound D, control impurity E 2, E3, E4.And then control the generation of impurity F 2, F3, F4.Reach the pressure alleviating end product purifying, the final object controlling quality product.Inevitably cause the loss of effective intermediate (impurity E 1).Indirectly cause reaction conversion ratio to reduce, reduce ultimate yield; Three be existing technical scheme solve an above-mentioned difficult problem way mainly according to be after Compound D deprotection and rearrangement reaction Pabuk former times profit cloth (Palbociclib) be a basic cpd; by (comparing example hydrochloric acid with multiple acid; methylsulphonic acid; Phenylsulfonic acid; tosic acid; hydroxyethylsulfonic acid, trifluoroacetic acid) after salify, carry out purification refine product.Those skilled in the art can understand, Pabuk former times profit cloth (Palbociclib) with above-mentioned acid group salify after, product increase all corresponding to each impurity polarity, be equivalent to pass through technical finesse, reduce Pabuk former times profit cloth (Palbociclib) and the polarity difference of each impurity, bring larger challenge to recrystallization or purifying.Separately because the polarity of Pabuk former times profit cloth (Palbociclib) with each impurity increases, cause selectable recrystallization solvent scope narrower, the present inventor states in solution processes on the implementation, recrystallizing methanol is used to Pabuk former times profit cloth (Palbociclib) single isethionate, after recrystallization three times, impurity is still had not reach the quality control requirement of regulation.
Table one: the impurity structure (part) that produces in Pabuk former times profit cloth (Palbociclib) preparation process
Route two: document
[7]disclosed the second prepares the method for Pabuk former times profit cloth (Palbociclib); its synthesis strategy adopts 2-ethanoyl-2-butylene acid methyl esters and propane dinitrile condensation cyclization under highly basic sodium methylate exists to prepare compound G; compound G uses highly basic sodium hydrogen and iodo pentamethylene to carry out alkylation and obtains compound H; compound H and Compound I take dimethylbenzene as solvent, and the reaction that high temperature 150 DEG C carries out 18-20 hour prepares compound J.Finally use sodium selenate to compound J in DMSO solvent, 150-160 DEG C is carried out oxidative dehydrogenation and prepares target product.Synthetic route (Pabuk former times profit cloth (Palbociclib) synthetic route two) is as follows:
The subject matter (defect) that this preparation method exists is: in the preparation process of compound G and compound H, employ highly basic sodium methylate and sodium hydrogen.Anhydrous response condition is harsh, and side reaction is many, and product is difficult to purifying; Two is rear two-step reaction (condensation and oxidations), all uses high boiling solvent.And temperature of reaction is 150-160 DEG C, and the reaction times very long (6-20 hour), temperature of reaction not only beyond product degradation temperature 110 DEG C, also brings very large potential safety hazard to suitability for industrialized production; Three is final step oxidizing reactions, and using poisonous heavy metal seleno oxide is oxygenant.Obvious is also inappropriate for preparation API.In view of present method Problems existing, not only operational condition is harsh obviously to adopt present method to prepare Pabuk former times profit cloth (Palbociclib), and product is easily degraded, and quality also cannot ensure.
By to the summary of prior art and evaluation, can determine that its preparation technology's difficulty is larger.The subject matter that the existing technical scheme preparing Pabuk former times profit cloth (Palbociclib) exists is summed up to get up to be mainly:
1., in the technical scheme of route one, use Pd catalyzer/Phosphine ligands and vinyl ether or its analogue to experience the linked reactions such as Heckreaction and Stillereaction and prepare in the process of Compound D, because temperature of reaction is higher, the time is longer; Employ Pd catalyzer/Phosphine ligands.Bring into multiple to target product polar phase like the impurity that, solubleness is similar, inevitably cause the loss of effective intermediate.Indirectly cause reaction conversion ratio to reduce, reduce ultimate yield;
2. by (comparing example hydrochloric acid with multiple acid, methylsulphonic acid, Phenylsulfonic acid, tosic acid, hydroxyethylsulfonic acid, trifluoroacetic acid) after salify, product increase all corresponding to each impurity polarity, be equivalent to reduce Pabuk former times profit cloth (Palbociclib) and the polarity difference of each impurity, bring larger challenge to recrystallization or purifying.Separately because the polarity of Pabuk former times profit cloth (Palbociclib) with each impurity increases, cause selectable recrystallization solvent scope narrower;
3. Part Methods prepares Pabuk former times profit cloth (Palbociclib) needs to use highly basic sodium methylate and sodium hydrogen.Anhydrous response condition is harsh, and side reaction is many, and product is difficult to purifying;
4. the using highly toxic substance and adopt high temperature etc. to operation and the very high reaction conditions of equipment requirements of Part Methods, produces to large-scale industrial and brings very large uncontrollability.
In sum, find or develop new, it is necessary for being better than the existing method preparing Pabuk former times profit cloth (Palbociclib).
Summary of the invention
For can overcome art methods prepare Pabuk former times profit cloth (Palbociclib) raw material availability low, complex operation, severe reaction conditions, production unit requires high, yield is low, high in cost of production defect, that the present invention is intended to provide a kind of reaction conditions easy, synthetic route is simple, yield is high, and the novel method of high purity Pabuk former times profit cloth can be prepared.
The present invention is realized by technical scheme below:
One prepares the method for compound Pabuk former times profit cloth (formula I), it is characterized in that, comprises the following steps:
With Compound D (formula II) for raw material, by the rearrangement reaction of alkene ether, obtain compd E (formula III), then compd E is sloughed in acid condition tertbutyloxycarbonyl protecting group (protecting hereinafter referred to as de-Boc), obtain target product Pabuk former times profit cloth (formula I); R group in Compound D is selected from C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
3-C
7any one in cycloalkyl.
Above-mentioned technological process can represent with following chemical equation:
Preferably, the invention provides a kind of method prepared, comprise the following steps:
(1) Compound D mix with certain proportion with acid in the first organic solvent, carry out the rearrangement reaction of alkene ether, react after terminating, crystallisation by cooling and/or add the second organic solvent and carry out recrystallization, obtain faint yellow to yellow solid compound E;
(2) compd E of step (1) gained dissolved or be suspended in the 3rd organic solvent, add a certain amount of acid to react, after completion of the reaction, obtain reaction mixture, by above-mentioned reaction mixture cooling, crystallization, filtration, get filter residue to be dried, obtain Pabuk former times profit cloth free alkali; Or regulate above-mentioned reaction mixture pH value with alkaline solution, then extract, extract is concentrated, dry, obtain Pabuk former times profit cloth free alkali.
Preferably, purity >=80% of described Compound D; Preferred, purity >=90%; Preferred, purity >=95%; Preferred, purity >=99.5%;
Preferably, purity >=98% of described compd E; Preferably, purity >=99.5%;
Preferably, described acid be selected from the acid of 1≤PKa≤5 any one; Preferably, described acid is selected from any one in mineral acid or organic acid; Further preferably, described mineral acid is selected from any one in hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid; Described organic acid be selected from the acid of 1≤carbon atom quantity≤7 any one, further preferred, be selected from trichlorine gifblaar poison, trichoroacetic acid(TCA), dichloro acetic acid, methylsulfonic acid, oxyacetic acid, hydroxyethylsulfonic acid, formic acid, acetic acid, oxalic acid, propionic acid, propanedioic acid any one; Preferred, be selected from hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, methylsulfonic acid, oxyacetic acid, hydroxyethylsulfonic acid any one; Preferred, be selected from hydrochloric acid, acetic acid, hydroxyethylsulfonic acid, trifluoroacetic acid, methylsulfonic acid any one.
Preferably, when described acid is PKa < 2 sour, described acid and Compound D mole dosage are than being 0.5-1.5:1, and preferably, mole dosage ratio is 0.8 ~ 1.2:1; When described acid is 2 < PKa≤5 sour, described acid is 5 ~ 100:1 with Compound D mole dosage ratio, and preferably, mole dosage ratio is 20 ~ 70:1.
Preferably, the first organic solvent described in step (1) is selected from any one in methyl alcohol, ethanol, Virahol, propyl carbinol, acetone, acetonitrile, tetrahydrofuran (THF), ethyl acetate, methylene dichloride, toluene, acetic acid, formic acid; Preferably, be selected from methyl alcohol, ethanol, propyl carbinol, ethyl acetate any one.
Preferably, the second organic solvent described in step (1) is selected from any one in normal hexane, normal heptane, sherwood oil, isopropyl ether, methyl tertiary butyl ether.
Preferably, the 3rd organic solvent described in step (2) to be selected from methyl alcohol, ethanol, Virahol, propyl carbinol, acetone, acetonitrile, tetrahydrofuran (THF), ethyl acetate, methylene dichloride, toluene, water, phenylmethylether any one or multiple; Preferably, the third solvent is selected from one or more the mixture in water, methyl alcohol or ethanol.
Preferably, the volume/weight ratio (ml/g) of the first organic solvent and Compound D described in step (1) is 5 ~ 50:1; Preferably, volume/weight ratio (ml/g) is 10 ~ 30:1.
Preferably, the 3rd organic solvent described in step (2) and the volume/weight ratio (ml/g) of Compound D are 5 ~ 50:1; Preferably, volume/weight ratio is 10 ~ 30:1.
Preferably, the temperature of reaction described in step (1) is 0 ~ 100 DEG C; Preferably, temperature of reaction is 25 ~ 80 DEG C.
Preferably, the reaction times described in step (1) is 1 ~ 48 hour; Preferably, the reaction times is 1 ~ 24 hour.
Preferably, the reaction times described in step (2) is 1 ~ 12 hour; Preferably, the reaction times is 2 ~ 6 hours.
Preferably, the pH described in step (2) is 9 ~ 13, and further preferably, described pH is 10 ~ 11;
Preferably, described in step (2) for regulating the alkali of pH to be sodium hydroxide or potassium hydroxide; Preferably, described alkali is sodium hydroxide.
Compared with prior art, the present invention has following technical superiority:
One, prior art prepares the scheme of Pabuk former times profit cloth is directly use greatly excessive strong acid to carry out rearrangement and the deprotection reaction of non-selectivity.Though the step of reaction can be shortened, need to Compound D or Pabuk former times profit cloth or its salt carry out repeatedly crystallization and purifying.Polishing purification Compound D not only itself causes Compound D to lose, and also causes the compd E (accounting for 5-15%) produced in Compound D preparation process to be treated as Impurity removal.Because Pabuk former times profit cloth is insoluble drug, polishing purification difficulty.Thus cause final total recovery to decline to a great extent and operating process increases.The actual object not reaching minimizing operation.And the new synthetic route of the present invention's design; take Compound D as raw material; first selectivity carries out the rearrangement reaction of alkene ether; obtain compd E; if desired purifying is carried out to compd E; obtain highly purified compd E, finally de-Boc protection in acid condition, can obtain profit cloth of highly purified Pabuk former times without the need to further purifying.Technical solution of the present invention is creationary makes Pabuk former times profit cloth intermediate (i.e. Compound D) containing two groups to acid all sensitivity, carried out substep optionally to react, one is the object of the impurity (compd E) that can reach in Appropriate application Compound D, and two is prepare the object that solvent system that compd E adopts also can reach purifying.What play is the effect of " 1+1 > 2 ".Alleviate the pressure of follow-up polishing purification, improve yield, decrease subsequent process steps.Adopt new technical scheme provided by the invention higher total recovery (70-80%) Pabuk former times profit cloth can be obtained.The total recovery height 15-20% that prior art prepares compd A is implemented than the present inventor.
Two, prior art does not have compd E purifying or the method obtaining high-purity compound E.The present inventor, by selective reaction, carries out solubility test to the compd E obtained, within finding compd E normal temperature or 100 DEG C, common organic solvents in testing laboratory or suitability for industrialized production, comprises methyl alcohol, ethanol, Virahol, propyl carbinol, acetone, acetonitrile, tetrahydrofuran (THF), ethyl acetate, methylene dichloride, toluene, acetic acid, formic acid etc. have good solubleness.Thus provide the difficulty selecting and reduce purifying widely for the polishing purification of compd E.And after experiencing rearrangement reaction, the polarity of compd E is larger a little than Compound D, sees theoretically, compd E and impurity E 1, E2, E3 (polarity) dissolubility difference are widened, and are also more conducive to carrying out recrystallization purifying.
Three, prior art is prepared in the process of Pabuk former times profit cloth, for solution Pabuk former times profit cloth free alkali solubleness is low, is difficult to the shortcoming of polishing purification.For the mode of employing Pabuk former times profit cloth and corresponding acid group salify is refined indirectly.Effect is not very desirable and solvent usage quantity is large, and yield is low.And the compd E that the present invention prepares, because the group alkene ether more responsive to acid completes rearrangement.And the acid that Boc protecting group is larger to some PKa values, can tolerate.Therefore compd E not only can adopt above solvent to carry out recrystallization, also the mixed system of organic acid or organic acid and above-mentioned solvent can be used, namely can by changing the pH value of recrystallization solvent, reach and better gone deimpurity object, PKa simultaneously due to acid is comparatively large, compd E not with organic acid salify.Purifying is carried out to Compound D and then rearrangement reaction can occur.Its purification effect and purifying compounds E effectiveness comparison, inferior position is apparent.
Four, technical scheme provided by the invention, the omnidistance strong acid not using high density, the corrosive liquid such as highly basic, no matter all operations condition all has very strong operability and controllability in testing laboratory or large-scale industrial production.Some the such as raw material availabilities overcoming prior art existence are low, complex operation, severe reaction conditions, and production unit requires high, and yield is low, and high in cost of production defect or difficulty, have a good application prospect.
Accompanying drawing explanation
Fig. 1: Pabuk former times profit cloth synthesis route figure.
Embodiment
Below in conjunction with several preferred embodiment, technical solution of the present invention is further non-limitingly described in detail.
Embodiment one:
Under room temperature, in dry reaction bottle, add Compound D 1 (C
30h
39n
7o
45.6g, 10mmol, purity>=99.5%), HCl (7.3g, 200mmol), CH
3oH (56.1ml) slowly mixes, stirring reaction 12h at 80 DEG C, after question response terminates, by mixture cooling crystallization, then adds a small amount of CH
3the mixed solvent of OH and sherwood oil carries out recrystallization, obtains faint yellow solid E.Then solid E is suspended in C
2h
5in OH (57.0ml), then drip HCl (7.3g, 200mmol), stirring reaction 6h at 80 DEG C, after question response terminates, adds NaOH and regulates pH11, cooling crystallization, suction filtration, is drying to obtain sterling Pabuk former times profit cloth free alkali 3.5g, yield 78%; Mass spectrum (EI): m/z448 (M+H).
Embodiment two:
Under room temperature, in dry reaction bottle, add Compound D 2 (C
33h
45n
7o
47.2g, 12mmol, purity>=99.5%), HCl (12.0g, 600mmol), CH
3oH (217.0ml) slowly mixes, stirring reaction 18h at 60 DEG C, after question response terminates, by mixture cooling crystallization, then adds a small amount of CH
3the mixed solvent of OH and sherwood oil carries out recrystallization, obtains yellow solid E.Then solid E is suspended in C
2h
5in OH (220.0ml), then drip HCl (12.0g, 600mmol), stirring reaction 6h at 80 DEG C, after question response terminates, cooling crystallization, suction filtration, is drying to obtain sterling Pabuk former times profit cloth free alkali 4.2g, yield 79%; Mass spectrum (EI): m/z448 (M+H).
Embodiment three:
Under room temperature, in dry reaction bottle, add compound d3 (C
31h
40clN
7o
46.1g, 10mmol, purity>=99.5%), CH
3cOOH (12.0g, 200mmol), CH
3oH (91.4ml) slowly mixes, stirring reaction 12h at 60 DEG C, after question response terminates, by mixture cooling crystallization, then adds a small amount of CH
3the mixed solvent of OH and sherwood oil carries out recrystallization, obtains faint yellow solid E.Then solid E is suspended in C
2h
5in OH (92.0ml), then drip HCl (7.3g, 200mol), stirring reaction 3h at 80 DEG C, after question response terminates, cooling crystallization, suction filtration, is drying to obtain sterling Pabuk former times profit cloth free alkali 3.4g, yield 76%; Mass spectrum (EI): m/z448 (M+H).
Embodiment four:
Under room temperature, in dry reaction bottle, add Compound D 4 (C
34h
47n
7o
46.2g, 10mmol, purity>=99.5%), CH
3cOOH (30.0g, 500mmol), CH
3oH (92.6ml) slowly mixes, stirring reaction 18h at 80 DEG C, after question response terminates, by mixture cooling crystallization, then adds a small amount of CH
3the mixed solvent of OH and sherwood oil carries out recrystallization, obtains yellow solid E.Then solid E is suspended in CH
3in OH (95.0ml), then drip HCl (18.3g, 500mmol), stirring reaction 3h at 80 DEG C, after question response terminates, cooling crystallization, suction filtration, is drying to obtain sterling Pabuk former times profit cloth free alkali 3.4g, yield 76%; Mass spectrum (EI): m/z448 (M+H).
Above embodiments of the invention have been described in detail, but described content is only preferred embodiment of the present invention, not in order to limit the present invention.All make in application range of the present invention any amendment, equivalent to replace and improvement etc., all should be included within protection scope of the present invention.
Claims (16)
1. prepare the method for compound Pabuk former times profit cloth (formula I), it is characterized in that, comprise the following steps:
With Compound D (formula II) for raw material, by the rearrangement reaction of alkene ether, obtain compd E (formula III), then compd E is sloughed tertbutyloxycarbonyl protecting group in acid condition, obtain target product Pabuk former times profit cloth (formula I); R group in Compound D is selected from C
1-C
6alkyl, C
1-C
6haloalkyl, C
1-C
6hydroxyalkyl, C
3-C
7any one in cycloalkyl.
2. preparation method according to claim 1, is characterized in that, comprises the following steps:
(1) Compound D mix with certain proportion with acid in the first organic solvent, carry out the rearrangement reaction of alkene ether, react after terminating, crystallisation by cooling and/or add the second organic solvent and carry out recrystallization, obtain faint yellow to yellow solid compound E;
(2) compd E of step (1) gained dissolved or be suspended in the 3rd organic solvent, add a certain amount of acid to react, after completion of the reaction, obtain reaction mixture, by above-mentioned reaction mixture cooling, crystallization, filtration, get filter residue to be dried, obtain Pabuk former times profit cloth free alkali; Or regulate above-mentioned reaction mixture pH value with alkaline solution, then extract, extract is concentrated, dry, obtain Pabuk former times profit cloth free alkali.
3. preparation method according to claim 1 and 2, is characterized in that, purity >=80% of described Compound D; Preferably, purity >=90%; Preferred, purity >=95%; Preferred, purity >=99.5%.
4. preparation method according to claim 1 and 2, is characterized in that, purity >=98% of described compd E; Preferably, purity >=99.5%.
5. preparation method according to claim 2, is characterized in that, described acid be selected from the acid of 1≤PKa≤5 any one; Preferably, described acid is selected from any one in mineral acid or organic acid; Further preferably, described mineral acid is selected from any one in hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid; Described organic acid be selected from the acid of 1≤carbon atom quantity≤7 any one, further preferred, be selected from trichlorine gifblaar poison, trichoroacetic acid(TCA), dichloro acetic acid, methylsulfonic acid, oxyacetic acid, hydroxyethylsulfonic acid, formic acid, acetic acid, oxalic acid, propionic acid, propanedioic acid any one; Preferred, be selected from hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, methylsulfonic acid, oxyacetic acid, hydroxyethylsulfonic acid any one; Preferred, be selected from hydrochloric acid, acetic acid, hydroxyethylsulfonic acid, trifluoroacetic acid, methylsulfonic acid any one.
6. preparation method according to claim 5, is characterized in that, when described acid is PKa < 2 sour, described acid and Compound D mole dosage are than being 0.5-1.5:1, and preferably, mole dosage ratio is 0.8 ~ 1.2:1; When described acid is 2 < PKa≤5 sour, described acid is 5 ~ 100:1 with Compound D mole dosage ratio, and preferably, mole dosage ratio is 20 ~ 70:1.
7. preparation method according to claim 2, it is characterized in that, the first organic solvent described in step (1) be selected from methyl alcohol, ethanol, Virahol, propyl carbinol, acetone, acetonitrile, tetrahydrofuran (THF), ethyl acetate, methylene dichloride, toluene, acetic acid, formic acid any one; Preferably, be selected from methyl alcohol, ethanol, propyl carbinol, ethyl acetate any one.
8. preparation method according to claim 2, is characterized in that, the second organic solvent described in step (1) be selected from normal hexane, normal heptane, sherwood oil, isopropyl ether, methyl tertiary butyl ether any one.
9. preparation method according to claim 2, it is characterized in that, the 3rd organic solvent described in step (2) to be selected from methyl alcohol, ethanol, Virahol, propyl carbinol, acetone, acetonitrile, tetrahydrofuran (THF), ethyl acetate, methylene dichloride, toluene, water, phenylmethylether any one or multiple mixture; Preferably, the third solvent is selected from one or more the mixture in water, methyl alcohol or ethanol.
10. preparation method according to claim 2, is characterized in that, the volume/weight ratio (ml/g) of the first organic solvent and Compound D described in step (1) is 5 ~ 50:1; Preferably, volume/weight ratio (ml/g) is 10 ~ 30:1.
11. preparation methods according to claim 2, the volume/weight ratio (ml/g) of the 3rd organic solvent described in step (2) and Compound D is 5 ~ 50:1; Preferably, volume/weight ratio is 10 ~ 30:1.
12. preparation methods according to claim 2, is characterized in that, the temperature of reaction described in step (1) is 0 ~ 100 DEG C; Preferably, temperature of reaction is 25 ~ 80 DEG C.
13. preparation methods according to claim 2, is characterized in that, the reaction times described in step (1) is 1 ~ 48 hour; Preferably, the reaction times is 1 ~ 24 hour.
14. preparation methods according to claim 2, is characterized in that, the reaction times described in step (2) is 1 ~ 12 hour; Preferably, the reaction times is 2 ~ 6 hours.
15. preparation methods according to claim 2, is characterized in that, the pH described in step (2) is 9 ~ 13, and further preferably, described pH is 10 ~ 11.
16. preparation methods according to claim 2 or 15, is characterized in that, for regulating the alkali of pH to be sodium hydroxide or potassium hydroxide described in step (2); Preferably, described alkali is sodium hydroxide.
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