The industrial manufacturing process of gemcitabine key intermediate sulfonation sugar
Technical field
The present invention relates to pharmaceutical synthesis field, and in particular to the industrially prepared work of gemcitabine key intermediate sulfonation sugar
Skill.
Background technology
Gemcitabine hydrochloride is cell cycle specific antimetabolitas, and it is as antitumoral compounds, U.S. in 1996
State FDA have approved first-line drug of the gemcitabine hydrochloride of Lilly Co., Eli.'s production as treatment cancer of pancreas, ratify within 1998
As treatment non-small cell lung cancer medicine.
Gemcitabine hydrochloride mainly acts on the tumour cell of DNA synthesis phases, i.e. S phase cells, under certain condition, can be with
Prevent progress of the G1 phases to the S phases;Its people and mouse tumour to various cultures has obvious cytotoxic activity, in non-lethal dose,
There is good active anticancer to the kinds of tumors of mouse.
The synthesis on gemcitabine hydrochloride of document report at present is mostly the D- Erythro-2,3-octadecane-diols with hydroxyl protection ', 2 '-two
Fluoro- 1- carbonyls ribose is intermediate.L.W.Hertel et al. is raw material first with R-2,3-O- contracting Acetone-glycerols aldehyde, synthesis
D- Erythro-2,3-octadecane-diols '-deoxidation -2 ', 2 '-two fluoro- 3 ', 5 '-O- tertiary butyls dimethyl silicon substrate -1- carbonyl ribose go forward side by side one-step synthesis
2 '-deoxidation -2 ', 2 '-difluoro glycosides urine (J.Org.Chem., 1988,2406).The reaction make use of the asymmetry that substrate controls
Reformatsky reacts, but selectivity is not high, it is necessary to further handle the reaction production that can just obtain chiral purity with column chromatography
Thing, this method are not suitable for industrially mass producing.
T.S.Chou et al. is improved above-mentioned route (Synthesis, 1992,565), by asymmetry
Reformatsky reactions are directly used in reaction along the mixture of anti-product, finally handle product with crystallisation, although the method avoids
Use column chromatography, but synthetic route is longer, product gross production rate is not high, and only 25% so that production cost improves.
It is raw material that Osamu Kitagawa, which are once attempted using iodo difluoro acetate, and adds trialkyl chlorine silicon in the reaction
The method of alkane improves the selectivity along anti-product, (Tetrahdron Lett., 1988,29,1803), Yasushi Matsumra
Et al. with (R) -2,3-O- contractings cyclohexanone-glyceraldehyde for raw material, in reaction system add Titanocene catalyst, Jin Erti
The high selectivity (J.Flurine chem., 1992,57,203) along anti-product, but these methods all employ it is expensive
Reagent, and severe reaction conditions, are not suitable for industrial production still.
The gemcitabine hydrochloride synthetic route of EP2018005A1 and CN20121004040.8 reports is with the D- of hydroxyl protection
Erythro-2,3-octadecane-diol ', 2 '-two fluoro- 1- carbonyls ribose are initiation material, and through carbonyl reduction, that hydroxyl sulfonation obtains 2- deoxidations -2,2- bis- is fluoro-
D- erythros-furan pentose -3,5- dibenzoate -1- methanesulfonates (α/β), with cytimidine be condensed after, Deprotection, into salt,
Crystallization purifies to obtain gemcitabine hydrochloride.The route carries out α and beta isomer purifying after synthesizing gemcitabine, and selectivity is not
Height, reaction yield is relatively low, and raw material availability is low, is not suitable for industrially mass producing.
Therefore, find a kind of preparation method that can ensure high-quality and high-efficiency has weight for industrial production gemcitabine hydrochloride
Want meaning.
The content of the invention
It is an object of the invention to solve above-mentioned technical problem, it is desirable to provide a kind of technique is simpler, and purity is good, and yield is high
Gemcitabine hydrochloride key intermediate sulfonation sugar, i.e. the preparation technology of formula (I) compound.
The preparation method of formula (I) compound provided by the invention, formula (IV) compound (α/β isomer mixture) is dissolved in
Organic solvent, cool precipitation formula (I) compound,
Wherein, R1, R2, R3 are hydroxyl protecting groups.
R1 is selected from mesyl, benzylsulphonyl or p-toluenesulfonyl, preferably mesyl;R2 is selected from formoxyl, second
Acyl group, benzoyl or to methyl benzoyl, preferably benzoyl;R2 is selected from formoxyl, acetyl group, benzoyl or to first
Base benzoyl, preferably benzoyl.
The organic solvent of dissolution type (IV) compound is selected from C1-C6 alcohol, preferably methanol, ethanol, isopropanol or butanol, more
Preferred alcohol;The solution temperature of formula (IV) compound is 50-60 DEG C;The cooling Precipitation Temperature of formula (I) compound is 28-33 DEG C,
It is preferred that 31 DEG C.
Further specifically, formula (I) compounds process for production thereof provided by the invention comprises the following steps:
A, formula (II) compound is reduced to formula (III) compound in the presence of additive and reducing agent,
B, the hydroxyl protection of formula (III) compound is obtained into formula (IV) compound,
C, formula (IV) compound is dissolved in organic solvent, cool precipitation formula (I) compound,
Wherein, R1, R2, R3 are hydroxyl protecting groups.
R1 is selected from mesyl, benzylsulphonyl or p-toluenesulfonyl, preferably mesyl;R2 is selected from formoxyl, second
Acyl group, benzoyl or to methyl benzoyl, preferably benzoyl;R2 is selected from formoxyl, acetyl group, benzoyl or to first
Base benzoyl, preferably benzoyl.
Preferably, step a reducing agent is sodium borohydride, and additive is zinc chloride and the tert-butyl alcohol;Step a reaction dissolvent
Selected from ethyl acetate and/or tetrahydrofuran, more preferably ethyl acetate and tetrahydrofuran volume ratio is 3:1 mixed solvent.
Preferably, the organic solvent of dissolution type (IV) compound is selected from C1-C6 alcohol, preferred alcohol in step c;Formula (IV)
The solution temperature of compound is 50-60 DEG C;The cooling Precipitation Temperature of formula (I) compound is 28-33 DEG C, preferably 31 DEG C.
The preparation technology of the present invention mainly has the following advantages that:
1st, combined from the go back original reagent of sodium borohydride/zinc chloride/tert-butyl alcohol, not only reaction efficiency is higher, also improves
The ratio of formula (III) compound α/β isomers, realize the effect of selective reduction.
2nd, the method for formula (IV) compound provided by the invention recrystallization resolution of alpha/beta isomer, not only have stronger pure
Change effect and split efficiency high, it is extremely low that fractionation obtains formula (I) compound purity height, content of isomer.
3rd, the method that gemcitabine hydrochloride resolution of alpha/beta isomer is repeatedly purified compared to prior art, the present invention is with tying again
Brilliant method splits to obtain formula (I) compound to formula (IV) compound progress α/β isomers, is further reacted with cytimidine
Target product gemcitabine, αisomer content is extremely low in gained target product, without further resolving and purifying.
Embodiment
In order to further illustrate the technique effect of technical scheme and its acquirement, below in conjunction with specific implementation
The present invention will be further described for example, but the scope of the present invention is not limited to embodiment.
Embodiment 1
Ethyl acetate 45mL, tetrahydrofuran 15mL are added into reaction bulb, add bis- fluoro- D- erythros-furans of 2- deoxidations -2,2-
Pentose -1- ketone -3,5- dibenzoate 10g, anhydrous zinc chloride 1.8, stirring and dissolving add tert-butyl alcohol 2g, and temperature control is less than 15 DEG C
Sodium borohydride 0.67g is added, is reacted 1 to 1.5 hour.Reaction finishes, and adds watery hydrochloric acid 40mL, stirs 10 minutes, stratification,
Abandon water layer, organic layer are washed with saturated brine 20mL, saturated sodium bicarbonate aqueous solution 20mL respectively, mistake after anhydrous magnesium sulfate is dried
Filter, concentration, obtains 2- deoxidation -2,2- difluoro-D-ribofuranose -3,5- dibenzoate 10g, α/β=3.7, yield 100%.
Embodiment 2
Ethyl acetate 45mL, tetrahydrofuran 15mL are added into reaction bulb, add bis- fluoro- D- erythros-furans of 2- deoxidations -2,2-
Pentose -1- ketone -3,5- diacetate esters 10g, anhydrous zinc chloride 1.8, stirring and dissolving add tert-butyl alcohol 2g, and temperature control adds less than 15 DEG C
Enter sodium borohydride 0.67g, react 1 to 1.5 hour.Reaction finishes, and adds watery hydrochloric acid 40mL, stirs 10 minutes, stratification, abandons
Water layer, organic layer are washed with saturated brine 20mL, saturated sodium bicarbonate aqueous solution 20mL respectively, mistake after anhydrous magnesium sulfate is dried
Filter, concentration, obtains 2- deoxidation -2,2- difluoro-D-ribofuranose -3,5- diacetate esters 10g, α/β=3.1, yield 100%.
Embodiment 3
Ethyl acetate 60mL is added into reaction bulb, adds bis- fluoro- D- erythros of 2- deoxidations -2,2--furan pentose -1- ketone -3,
5- dibenzoate 10g, anhydrous zinc chloride 1.8, stirring and dissolving, add tert-butyl alcohol 2g, less than 15 DEG C addition sodium borohydrides of temperature control
0.67g, react 1 to 1.5 hour.Reaction finishes, and adds watery hydrochloric acid 40mL, stirs 10 minutes, stratification, and abandon water layer is organic
Layer is washed with saturated brine 20mL, saturated sodium bicarbonate aqueous solution 20mL respectively, and anhydrous magnesium sulfate filters after drying, and is concentrated, is obtained
2- deoxidation -2,2- difluoro-D-ribofuranose -3,5- dibenzoate 10g, α/β=3.1, yield 100%.
Embodiment 4
Tetrahydrofuran 60mL is added into reaction bulb, adds bis- fluoro- D- erythros of 2- deoxidations -2,2--furan pentose -1- ketone -3,
5- dibenzoate 10g, anhydrous zinc chloride 1.8, stirring and dissolving, add tert-butyl alcohol 2g, less than 15 DEG C addition sodium borohydrides of temperature control
0.67g, react 1 to 1.5 hour.Reaction finishes, and adds watery hydrochloric acid 40mL, stirs 10 minutes, stratification, and abandon water layer is organic
Layer is washed with saturated brine 20mL, saturated sodium bicarbonate aqueous solution 20mL respectively, and anhydrous magnesium sulfate filters after drying, and is concentrated, is obtained
2- deoxidation -2,2- difluoro-D-ribofuranose -3,5- dibenzoate 10g, α/β=3.3, yield 100%.
Embodiment 5
By 2- deoxidation -2,2- difluoro-D-ribofuranose -3,5- dibenzoates 10g, triethylamine 5.4ml, dichloromethane
100mL is mixed, and is cooled to 5-10 DEG C, mesyl chloride 2.2ml is added dropwise in less than 15 DEG C in temperature control, and cryostat, room are removed after being added dropwise
Warm stirring reaction 2h, after reaction terminates, successively with 1M hydrochloric acid, saturated sodium bicarbonate solution and saturated common salt water washing, organic phase
With anhydrous sodium sulfate drying, concentration, the double benzoic ether -1- methanesulfonates of 2- deoxidations -2,2- difluoro-D-ribofuranose -3,5- are obtained
10.8g, α/β=3.8, yield 91.8%.
Embodiment 6
Double benzoic ether -1- methanesulfonates the 10g (α/β=4.8) of 2- deoxidation -2,2- difluoro-D-ribofuranoses -3,5- are added
Enter in reaction bulb, add ethanol 100mL, be heated to 50 to 60 DEG C of dissolved clarifications, 31 DEG C of crystallizations are cooled to after dissolved clarification 1 to 2 hour, mistake
Filter, solid it is dry double benzoic ether -1- methanesulfonates 8.1g, the β isomeries of α -2- deoxidations -2,2- difluoro-D-ribofuranoses -3,5-
Body content 0.07%, yield 81%.
Embodiment 7
Double benzoic ether -1- methanesulfonates the 10g (α/β=4.8) of 2- deoxidation -2,2- difluoro-D-ribofuranoses -3,5- are added
Enter in reaction bulb, add methanol 100mL, be heated to 50 to 60 DEG C of dissolved clarifications, 28 DEG C of crystallizations are cooled to after dissolved clarification 1 to 2 hour, mistake
Filter, solid it is dry double benzoic ether -1- methanesulfonates 7.1g, the β isomeries of α -2- deoxidations -2,2- difluoro-D-ribofuranoses -3,5-
Body content 0.21%, yield 71%.
Embodiment 8
Double benzoic ether -1- methanesulfonates the 10g (α/β=4.8) of 2- deoxidation -2,2- difluoro-D-ribofuranoses -3,5- are added
Enter in reaction bulb, add isopropanol 100mL, be heated to 50 to 60 DEG C of dissolved clarifications, 33 DEG C of crystallizations are cooled to after dissolved clarification 1 to 2 hour, mistake
Filter, solid it is dry double benzoic ether -1- methanesulfonates 7.4g, the β isomeries of α -2- deoxidations -2,2- difluoro-D-ribofuranoses -3,5-
Body content 0.09%, yield 74%.
Embodiment 9
Double benzoic ether -1- methanesulfonates the 10g (α/β=4.1) of 2- deoxidation -2,2- difluoro-D-ribofuranoses -3,5- are added
Enter in reaction bulb, add ethanol 100mL, be heated to 50 to 60 DEG C of dissolved clarifications, 31 DEG C of crystallizations are cooled to after dissolved clarification 1 to 2 hour, mistake
Filter, solid it is dry double benzoic ether -1- methanesulfonates 7.8g, the β isomeries of α -2- deoxidations -2,2- difluoro-D-ribofuranoses -3,5-
Body content 0.08%, yield 78%.
Embodiment 10
By cytimidine (24.4g, 0.22mol), HMDS (46.2mL, 0.22mol) and ammonium sulfate (0.03g)
Mixed in 2L there-necked flasks, be heated to reflux to reaction solution after clarifying, continue insulation reaction 30min.Less than 80 DEG C are cooled to, decompression
Solvent is evaporated off, separates out solid.Add Me3SiOTf (48.9g, 0.22mol), methyl phenyl ethers anisole (400ml), heating stirring make solid molten
Solution.Added in reaction solution the double benzoic ether -1- methanesulfonates of α -2- deoxidations -2,2- difluoro-D-ribofuranoses -3,5- (90.0g,
0.20mol, beta isomer content 0.07%), the mixed solution of methyl phenyl ethers anisole (200ml), 120 DEG C reaction 3h, TLC detection reaction knot
Beam, ethyl acetate (500ml) dilution is added after being cooled to room temperature, stirring, 4M hydrochloric acid (300mL) is added dropwise, is warming up to 70 DEG C of guarantors afterwards
Warm 2h.Filter while hot, filter cake is beaten 1h then at 70 DEG C of water, filters while hot, and filter cake adds water (300mL) to suspend and with 5% bicarbonate
Sodium solution adjust pH to 7, filtering, after vacuum drying Gemzart -3 ', 5 '-dibenzoate 80.6g, α
Content of isomer 0.08%, yield 85.5%.
Embodiment 11
By Gemzart -3 ', 5 '-dibenzoate (75.0g, 0.16mol, αisomer content
0.08%), sodium tert-butoxide (33.6g, 0.34mol), methanol (800ml) mix in 2L there-necked flasks, react at room temperature 2h, TLC inspections
Survey reaction terminate, 1M hydrochloric acid adjust pH to 7, be concentrated under reduced pressure into it is dry, add water (1L), removal of impurities is extracted with ethyl acetate, afterwards acetic acid
The a small amount of water backwash of methacrylate layer, combining water layer, activated carbon decolorizing, filtering, filtrate is spin-dried for, added in residue isopropanol (1L) and
Concentrated hydrochloric acid (40ml), 70 DEG C are heated to, room temperature is stood overnight after being incubated 30min.Filtering, filter cake use cold isopropanol and just oneself successively
Alkane washs, and dries, obtains gemcitabine hydrochloride 44.8g, purity 99.5%, αisomer content 0.02%, yield 93.4%.
1H NMR(DMSO-d6)δ:10.40 (s, 1H, OH-2), 9.00 (s, 1H, OH-4), 8.20 (d, J=8.29Hz,
1H, H-9), 6.32 (br, 2H, NH2), 6.31 (d, J=8.29Hz, 1H, H-8), 6.08 (t, 1H, H-5), 4.22 (m, 1H, H-
2),3.93(m,1H,H-3),3.80(dd,1H,H-4),3.66(dd,1H,H-4);13C NMR(DMSO-d6)δ:159.56(C-
7),146.78(C-6),143.42(C-9),122.8(C-1),94.7(C-8),83.8(C-5),81.59(C-3),68.1(C-
2),58.69(C-4);MS-ESI(m/z):264.0[M+H]+ .