CN105503765A - Posaconazole, composition, intermediate, preparation method and application thereof - Google Patents
Posaconazole, composition, intermediate, preparation method and application thereof Download PDFInfo
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- CN105503765A CN105503765A CN201410505311.3A CN201410505311A CN105503765A CN 105503765 A CN105503765 A CN 105503765A CN 201410505311 A CN201410505311 A CN 201410505311A CN 105503765 A CN105503765 A CN 105503765A
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- 0 C[C@](C*C=C(C)[C@@]1OC[C@@](CO)C[C@@]1C)CF Chemical compound C[C@](C*C=C(C)[C@@]1OC[C@@](CO)C[C@@]1C)CF 0.000 description 10
- AEKBJBNRZGVHBJ-UHFFFAOYSA-N C=C(CCC(O)=O)c(c(F)c1)ccc1F Chemical compound C=C(CCC(O)=O)c(c(F)c1)ccc1F AEKBJBNRZGVHBJ-UHFFFAOYSA-N 0.000 description 1
- HGHKXIOBIUJSCS-UHFFFAOYSA-N CCCOCc1ccc(C)cc1 Chemical compound CCCOCc1ccc(C)cc1 HGHKXIOBIUJSCS-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention relates to a compound as shown in the formula III, wherein R is selected from C1-C4 alkyl group, substituted or unsubstituted phenyl group and substituted or unsubstituted benzyl group, and is preferably selected from isopropyl group; and two Ar can be the same or different, respectively and separately selected from substituted or unsubstituted aryl group, and preferably selected from substituted or unsubstituted phenyl group, such as methoxyphenyl, etc. The compound is preferably in a solid form.
Description
Technical field
The present invention relates to medical art, in particular to posaconazole, composition, intermediate, its synthetic method and the purposes in synthesis posaconazole thereof.
Background technology
(CAS registration number is 171228-49-2 to posaconazole; CAS title: 2,5-dehydration-1,3,4-tri-deoxidation-2-C-(2,4-difluorophenyl)-4-[[4-[4-[1-(1S, 2S)-1-ethyl-2-hydroxypropyl]-1,5-dihydro-5-oxo-4H-1,2,4-triazole-4-yl] phenyl]-1-piperazinyl] phenoxy group] methyl]-1-(1H-1,2,4-triazol-1-yl)-D-Soviet Union-pentitol), for the invasive infections with fungi that prevention and therapy invasive infections with fungi, resistance or other drug are invalid, structure is as follows:
One of important intermediate preparing posaconazole is formula IX compound,
Wherein Q be replace or unsubstituted benzenesulfonyl, p-toluenesulfonyl or to chlorobenzenesulfonyl etc.The synthesis (one) of this intermediate is reported in patent US5403937A,
Be characterized in R-4-benzyl oxazolidone as chiral auxiliary, the compound (2) that acid (1) and R-4-benzyl oxazolidone are obtained by reacting is obtained compound (3) with the asymmetric hydroxy methylene of trioxymethylene under triethylamine and titanium tetrachloride mediate, with after obtain tetrahydrofuran (THF) intermediate (4) (cis/trans formula mol ratio is 85: 15 to 95: 5) through intramolecular iodine etherification reaction Stereoselective, remove chiral auxiliary through hydroboration Lithium reduction again and obtain iodohydrin intermediate (5), this technique respectively walks intermediate and is oily matter, especially intramolecular iodine ether ringization one step needs to use excessive iodine, not only price is high, and toxicity is large.Lithium borohydride removes chiral auxiliary in addition, not only reagent price, and the iodohydrin intermediate (5) obtained after reduction needs column chromatography for separation with chiral auxiliary, is unfavorable for suitability for industrialized production.
WO2013042138 reports the preparation method (two) of an other synthesis type X compound,
Be characterized in that R-4-oxazolyl phenyl alkane ketone is chiral auxiliary, sodium hydroxide and aquae hydrogenii dioxidi solution is utilized to remove prothetic group, although this route avoids column chromatography for separation to obtain acid iodide intermediate (formula-7) and chiral auxiliary, but compound formula-6 mono-step is prepared in iodo cyclization still to be needed to use excessive iodine, faces same problem with above-mentioned patent.Remove prothetic group one step due to will hydrogen peroxide be used with sodium hydroxide hydrolysis in addition, industrial production exists certain danger.
Summary of the invention
In order to solve the problem, contriver is through intensive research, find the chiral auxiliary utilizing formula II structure, make the easier crystallization of key intermediate, be convenient to purifying, and avoid using excessive halogen and the hydrolysis of prothetic group being removed in halo cyclization one step avoiding being used in the industrial hydrogen peroxide with potential safety hazard, making the recovery of prothetic group and solvent safer, thus reduce production cost, thus complete the present invention.
Technical scheme of the present invention includes but not limited to the following.
The compound of technical scheme 1: formula II,
Wherein,
R is selected from C
1-C
4alkyl, replacement or unsubstituted phenyl, replacement or unsubstituted benzyl, preferred sec.-propyl;
Two Ar can be identical or different, is selected from replacement or unsubstituted aryl independently of one another, preferably replace or unsubstituted phenyl, as p-methoxyphenyl.
Technical scheme 2: the compound of formula III,
Wherein,
R and Ar is as defined above.
The compound of technical scheme 3: formula IV,
Wherein,
R and Ar is as defined above,
Described compound is preferably solid form.
The compound of technical scheme 4: formula V,
Wherein,
R and Ar is as defined above; And
A is Br, Cl or I, preferred Br,
Described compound is preferably solid form.
The compound of technical scheme 5: formula VI,
Wherein,
A is selected from Cl or Br, preferred Br,
Described compound is preferably solid form.
The compound of technical scheme 6: formula VII,
Wherein,
A is selected from Cl or Br, preferred Br,
Described compound is preferably solid form.
Technical scheme 7: a kind of composition, the compound of the contained IX of described composition
Wherein,
Q is selected from replacement or unsubstituted benzenesulfonyl, preferred p-toluenesulfonyl, to chlorobenzenesulfonyl;
And the compound of formula X,
Wherein, relative to the total mass of composition, the mass percent of the compound of described formula IX is 95% to 100%, and the mass percent of described formula X is 0% to 5.0%,
Described composition is preferably solid form.
Technical scheme 14: a kind of method preparing the compound of formula III,
Described method comprises:
Make the compound of formula I and the compound generation acylation reaction of formula II,
Wherein,
R and Ar is as defined above.
Technical scheme 15: the method described in technical scheme 14, wherein said acylation reaction adopts one or more acylating reagents be selected from the following: oxalyl chloride, pivaloyl chloride, thionyl chloride, POCl
3, PCl
3, PCl
5, preferred oxalyl chloride, thionyl chloride or pivaloyl chloride.
Technical scheme 16: the method described in technical scheme 14; wherein said acylation reaction is carried out under the existence being selected from one or more alkali in the following: organometallic reagent is as butyllithium, diisopropylamine lithium, or the mixture of trimethylamine (as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine) and Lithium chloride (anhydrous).
Technical scheme 17: the method described in technical scheme 14, wherein said acylation reaction preferably at butyllithium, or is carried out under the existence of the mixture of pivaloyl chloride and triethylamine and Lithium chloride (anhydrous).
Technical scheme 18: the method described in technical scheme 14, wherein said acylation reaction is carried out under the existence of polar aprotic solvent, as chlorinated solvents, ether solvent, the one in preferred tetrahydrofuran (THF), methylene dichloride or its mixture.
Technical scheme 19: the method for the compound of a kind of preparation formula IV,
Described method comprises:
The compound trioxymethylene of formula III is carried out hydroxy methylene,
Wherein,
R is selected from C
1-C
4alkyl, replacement or unsubstituted phenyl, replacement or unsubstituted benzyl, preferred sec.-propyl;
Ar is selected from replacement or unsubstituted phenyl, as p-methoxyphenyl.
Technical scheme 20: the method according to technical scheme 19, wherein said hydroxy methylene carries out under organic bases and titanium tetrachloride effect.
Technical scheme 21: the method according to technical scheme 20, wherein said organic bases be selected from the following one or more: trimethylamine, as triethylamine, tri-tert amine, N-methylmorpholine, diisopropyl ethyl amine, preferred triethylamine or diisopropyl ethyl amine.
Technical scheme 22: the method according to technical scheme 19, wherein said hydroxy methylene carries out in by one or more solvents be selected from group that the following forms: aprotic solvent is as chlorinated solvents, esters solvent, ether solvent, preferred methylene dichloride, 1,2-ethylene dichloride.
Technical scheme 23: the method for the compound of a kind of preparation formula V,
Described method comprises:
The compound of formula IV and halide reagent are reacted,
Wherein,
R and Ar is as defined above;
A is Br, Cl or I.
Technical scheme 24: the method described in technical scheme 23, wherein said reaction is carried out under neutral or basic conditions.
Technical scheme 25: the method described in technical scheme 23, wherein said halide reagent comprise be selected from the following one or more: halogen, preparing halogenated hydantoin, N-bromo-succinimide (NBS), N-N-iodosuccinimide (NIS), N-chlorosuccinimide (NCS), preferred iodine, NIS bromine, NBS or C5H6Br2N2O2.
Technical scheme 26: the method described in technical scheme 23, wherein said reaction is carried out under the existence being selected from one or more the alkali in the following: alkali metal hydroxide, metal carbonate compound, metal carbonate hydride, preferred sodium bicarbonate.
Technical scheme 27: the method described in technical scheme 23, wherein said reaction is carried out being selected from one or more solvents in the group be made up of the following: polar aprotic solvent is if tetrahydrofuran (THF), acetonitrile, ethyl acetate and protonic solvent are as water, alcoholic solvent, the mixture of preferred tetrahydrofuran (THF) and water.
Technical scheme 28: the method for the compound of a kind of preparation formula VI,
Described method comprises:
By the compound hydrolysis of formula V,
Wherein,
R and Ar is as defined above;
A is Br, Cl or I.
Technical scheme 29: the method according to technical scheme 28, wherein said hydrolysis is carried out in the basic conditions.
Technical scheme 30: the method according to technical scheme 28, wherein said hydrolysis is carried out under the existence being selected from one or more alkali in the following: alkali metal hydroxide, metal carbonate compound, preferred sodium hydroxide.
Technical scheme 31: the method according to technical scheme 28, wherein said hydrolysis is carried out being selected from one or more solvents in the group be made up of the following: the mixture of polar organic proton or non-protonic solvent and water, preferred tetrahydrofuran (THF) and water.
Technical scheme 32: the method for the compound of a kind of preparation formula VII,
Described method comprises:
The compound of formula V is reduced,
Wherein,
R is selected from C
1-C
4alkyl, replacement or unsubstituted phenyl, replacement or unsubstituted benzyl, preferred sec.-propyl;
Ar is selected from replacement or unsubstituted phenyl, as p-methoxyphenyl;
A is Br, Cl or I.
Technical scheme 33: the method described in technical scheme 32, wherein said reduction hydrogenation uses one or more the reductive agent be selected from the following: hydride reducer, preferred lithium borohydride.
Technical scheme 34: the method described in technical scheme 32, wherein said reduction is carried out in by one or more solvents formed be selected from the following: methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), 2-methyltetrahydrofuran, methylene dichloride and ethyl acetate.
Technical scheme 35: the method for the compound of a kind of preparation formula VII,
Described method comprises:
The compound of formula VI is reduced,
Wherein,
A is Br or Cl.
Technical scheme 36: the method described in technical scheme 35, wherein said reduction uses one or more reductive agents be selected from the following: diisobutyl aluminium hydride, sodium borohydride, lithium borohydride, sodium borohydride/BF
3-ether, vitride, sodium borohydride/aluminum chloride or borine/aluminum chloride, sodium borohydride/iodine, red aluminum solutions.
Technical scheme 37: the method described in technical scheme 35, wherein said reduction is carried out being selected from one or more solvents in the group be made up of the following: organic dipolar aprotic solvent, as tetrahydrofuran (THF), toluene, methylene dichloride, preferred tetrahydrofuran (THF), toluene.
Technical scheme 38: the method for the compound of a kind of preparation formula IX,
Said method comprising the steps of:
G) compound of formula VII and 1,2,3-triazole an alkali metal salt or 1,2,3-triazole is made to react,
The compound of production VIII,
F) by the compound sulfonylation of formula VIII;
Wherein,
Q is selected from replacement or unsubstituted benzenesulfonyl, preferred p-toluenesulfonyl, to chlorobenzenesulfonyl;
A is Br;
Described method also optionally comprises the following steps:
The compound of the method preparation formula VII according to any one in technical scheme 32 to 37.
Technical scheme 39: the method described in technical scheme 38, wherein step g) carry out under the existence being selected from one or more alkali in the following: metal hydride, metal alcoholate, metal carbonate compound, as NaH, KH, sodium alkoxide, Na
2cO
3, K
2cO
3.
Technical scheme 40: the method described in technical scheme 38, wherein said step g) carry out under the existence being selected from one or more catalyzer in the following: crown ether, as 15-hat-5,18-hat-6, tetrabutylammonium iodide, catalytic amount KI, NaI.
Technical scheme 41: the method described in technical scheme 38, wherein said step g) carry out being selected from one or more solvents in the group be made up of the following: dipolar aprotic solvent, as dimethyl sulfoxide (DMSO), N, dinethylformamide, N,N-dimethylacetamide, N-Methyl pyrrolidone.
Technical scheme 42: the method described in technical scheme 38, wherein said sulfonylation uses QX as sulfonylation agent,
Wherein,
Q is selected from replacement or unsubstituted benzenesulfonyl, preferred p-toluenesulfonyl, to chlorobenzenesulfonyl;
X is Br, Cl or I.
Technical scheme 43: the method described in technical scheme 38; wherein said sulfonylation carries out under the existence being selected from one or more alkali in the following: organic bases; as triethylamine, tributylamine, DMAP, N-methylmorpholine, diisopropylethylamine, preferred diisopropylethylamine.
Technical scheme 44: the method described in technical scheme 38, wherein said sulfonylation carries out being selected from one or more solvents in the group be made up of the following: chlorinated solvent and varsol, preferred methylene dichloride, toluene, tetrahydrofuran (THF).
Technical scheme 45: a kind of method preparing the composition of the compound of contained IX,
Said method comprising the steps of:
G) compound of formula VII and 1,2,3-triazole an alkali metal salt or 1,2,3-triazole is made to react,
Wherein,
A is Br, Cl or I,
The compound of production VIII,
F) by the compound sulfonylation of formula VIII;
G) recrystallization;
Obtain
The compound of contained IX, and the compound of contained X,
Wherein, relative to the total mass of composition, the mass percent of the compound of described formula IX is 95% to 100%, and the mass percent of described formula X is 0% to 5.0%,
Described composition is preferably solid form.
Technical scheme 46: the method described in technical scheme 45, wherein step g) carry out under the existence being selected from one or more alkali in the following: metal hydride, metal alcoholate, metal carbonate compound, as NaH, KH, sodium alkoxide, Na
2cO
3, K
2cO
3.
Technical scheme 47: the method described in technical scheme 45, wherein A is Cl or Br, described step g) carry out under the existence being selected from one or more catalyzer in the following: crown ether, as 15-hat-5,18-hat-6, tetrabutylammonium iodide, catalytic amount KI, NaI.
Technical scheme 48: the method described in technical scheme 45, wherein said step g) carry out in by one or more solvents formed be selected from the following: dipolar aprotic solvent, as dimethyl sulfoxide (DMSO), N, dinethylformamide, N,N-dimethylacetamide, N-Methyl pyrrolidone.
Technical scheme 49: the method described in technical scheme 45, wherein said sulfonylation uses QX as sulfonylation agent,
Wherein,
Q is selected from replacement or unsubstituted benzenesulfonyl, preferred p-toluenesulfonyl, to chlorobenzenesulfonyl;
X is Br, Cl or I.
Technical scheme 50: the method described in technical scheme 45; wherein said sulfonylation carries out under the existence being selected from one or more alkali in the following: organic bases; as triethylamine, tributylamine, DMAP, N-methylmorpholine, diisopropylethylamine, preferred diisopropylethylamine.
Technical scheme 51: the method described in technical scheme 45, wherein said sulfonylation carries out in by one or more solvents formed be selected from the following: chlorinated solvent and varsol, preferred methylene dichloride, toluene, tetrahydrofuran (THF).
Technical scheme 52: the method described in any one in technical scheme 14 to 18, the compound of wherein said formula II is by the preparation of the method described in any one in technical scheme 8 to 13.
Technical scheme 53: the method described in any one in technical scheme 19 to 22, the compound of wherein said formula III is by the preparation of the method described in any one in technical scheme 14 to 18 and 52.
Technical scheme 54: the method described in any one in technical scheme 23 to 27, the compound of wherein said formula IV is by the preparation of the method described in any one in technical scheme 19 to 22 and 53.
Technical scheme 55: the method described in any one in technical scheme 28 to 31, the compound of wherein said formula V is by the preparation of the method described in any one in technical scheme 23 to 27 and 54.
Technical scheme 56: the method described in any one in technical scheme 32 to 34, the compound of wherein said formula V is by the preparation of the method described in any one in technical scheme 23 to 27 and 54.
Technical scheme 57: the method described in any one in technical scheme 35 to 37, the compound of wherein said formula VI is by the preparation of the method described in any one in technical scheme 28 to 31 and 55.
Technical scheme 58: the method described in any one in technical scheme 38 to 44, the compound of wherein said formula VII is by the method preparation described in technical scheme 56 or 57.
Technical scheme 59: the method described in any one in technical scheme 45 to 51, the compound of wherein said formula VII is by the preparation of the method described in any one in technical scheme 32 to 37 and 56 to 57.
Technical scheme 60: the compound described in technical scheme 1, described compound is by the preparation of the method described in any one in technical scheme 8 to 13.
Technical scheme 61: the compound described in technical scheme 2, described compound is by the preparation of the method described in any one in technical scheme 14 to 18 and 52.
Technical scheme 62: the compound described in technical scheme 3, described compound is by the preparation of the method described in any one in technical scheme 19 to 22 and 53.
Technical scheme 63: the compound described in technical scheme 4, described compound is by the preparation of the method described in any one in technical scheme 23 to 27 and 54.
Technical scheme 64: the compound described in technical scheme 5, described compound is by the preparation of the method described in any one in technical scheme 28 to 31 and 55.
Technical scheme 65: the compound described in technical scheme 6, described compound is by the preparation of the method described in any one in technical scheme 32 to 37 and 56 to 57.
The compound of technical scheme 66: formula IX
Wherein,
Q is selected from replacement or unsubstituted benzenesulfonyl, preferred p-toluenesulfonyl, to chlorobenzenesulfonyl;
The compound of described formula IX is by the preparation of the method described in any one in technical scheme 38 to 44 and 58.
Technical scheme 67: the solid-state composition described in technical scheme 7, described solid-state composition is by the preparation of the method described in any one in technical scheme 45 to 51 and 59.
Technical scheme 68: the compound described in any one in technical scheme 1 to 6 and 60 to 66 or the purposes of the composition described in technical scheme 7 or 67 in the synthesis of posaconazole.
Technical scheme 69: the compound described in any one in technical scheme 1 to 6 and 60 to 66 or the composition described in technical scheme 7 or 67, described compound or composition are used for the synthesis of posaconazole.
Technical scheme 70: a kind of method of synthesizing posaconazole, described method comprises the step by the compound described in the method technology of preparing scheme 1 described in any one in technical scheme 8 to 13.
Technical scheme 71: a kind of method of synthesizing posaconazole, described method comprises the step by the compound described in the method technology of preparing scheme 2 described in any one in technical scheme 14 to 18 and 52.
Technical scheme 72: a kind of method of synthesizing posaconazole, described method comprises the step by the compound described in the method technology of preparing scheme 3 described in any one in technical scheme 19 to 22 and 53.
Technical scheme 73: a kind of method of synthesizing posaconazole, described method comprises the step by the compound described in the method technology of preparing scheme 4 described in any one in technical scheme 23 to 27 and 54.
Technical scheme 74: a kind of method of synthesizing posaconazole, described method comprises the step by the compound described in the method technology of preparing scheme 5 described in any one in technical scheme 28 to 31 and 55.
Technical scheme 75: a kind of method of synthesizing posaconazole, described method comprises the step by the compound described in the method technology of preparing scheme 6 described in any one in technical scheme 32 to 37 and 56 to 57.
Technical scheme 76: a kind of method of synthesizing posaconazole, described method comprises the step of the compound by the method preparation formula IX described in any one in technical scheme 38 to 44 and 58,
Wherein,
Q is selected from replacement or unsubstituted benzenesulfonyl, preferred p-toluenesulfonyl, to chlorobenzenesulfonyl.
Technical scheme 77: a kind of method of synthesizing posaconazole, described method comprises the step by the solid-state composition described in the method technology of preparing scheme 7 described in any one in technical scheme 45 to 51 and 59.
Technical scheme 78: a kind of composition comprising posaconazole, described composition is got by the solid-state composition preparation described in technical scheme 7.
Technical scheme 79: the method for the synthesis posaconazole described in any one in technical scheme 70 to 77, said method comprising the steps of:
The compound of formula IX and the compound of formula A are reacted,
Wherein,
Q is selected from replacement or unsubstituted benzenesulfonyl, preferred p-toluenesulfonyl, to chlorobenzenesulfonyl;
The compound of production B,
And be posaconazole by the compound hydrolysis of formula B.
Technical scheme 80: the N crystal form of the compound of a kind of formula S,
Described N crystal form has XRD spectra as shown in Figure 1.
Technical scheme 81: the N crystal form of the compound of the formula S described in technical scheme 80, the N crystal form of the compound of described formula S is by the preparation of the method described in any one in technical scheme 70 to 77 or 79.
The composition described in any one in compound described in any one in technical scheme 82: technical scheme 1-6 and 60-66 and/or technical scheme 7,67,69 and 78 and/or the purposes of the method described in any one in the N crystal form of the compound of the formula S described in technology of preparing scheme 80 in technical scheme 8-59,70-77 and 79.
The method of the N crystal form of the compound of the formula S described in technical scheme 83. technology of preparing scheme 80, comprises the following steps:
Method described in technical scheme 84. technical scheme 83, wherein said solvent is selected from:.
Technical scheme 85: a kind of composition, it comprises posaconazole, and the compound of contained X,
Wherein, relative to the total mass of composition, the mass percent of the compound of described formula IX is 95% to 100%, and the mass percent of described formula X is 0% to 5.0%, and described posaconazole is preferably the N crystal form described in technical scheme 80 or 81.
In one aspect of the invention, by technical scheme of the present invention, can obtain intermediate compound IV and V in solid form, it is separated is extremely facilitate with efficiently, thus can obtain high purity intermediate VII.
Accompanying drawing explanation
Fig. 1 is the XRD spectra of the N crystal form of the compound of formula S, wherein:
Peak position (34 peaks, maximum P/N=110.6)
Peak: 21-pts/ para-curve filter, threshold value=3.0, block=0.1%, BG=3/1.0,
Peak-top=vertex
2-θ d (A) BG height I% area I%FWHM
6.00114.7158611048698.66086780.213
7.8211.296769801543727.4327843430.361
9.7799.0372592931035.5504336.60.276
11.7597.519448564132973.476034799.70.313
13.7396.4443162117437.643188956.60.347
15.545.6976483978591413210817.30.286
16.2815.4397518045708.1511346.70.19
16.9995.211550161525127.120776827.30.232
17.8994.95145654926316.513051217.10.24
18.44.817953272087437.131808041.70.259
18.9614.67646188962217.1114080150.202
19.8414.471567549538.814666819.20.503
20.164.40115685728712.915164819.90.354
21.5794.114661773587463.750673266.50.24
22.963.870367951166520.718603424.40.271
24.5183.6277782129195.299013130.577
25.0393.55348471563101007624071000.23
25.723.4608845746068.213357717.50.493
26.0783.414180011005417.9205987270.348
26.83.3237705942937.6661178.70.262
27.683.22016438813914.511505015.10.24
28.83.0973625538556.8596937.80.263
29.4193.0336594629945.3597227.80.339
29.922.9839606013292.4197062.60.252
31.1992.8644524323764.24582360.328
32.1192.784551719651.7144211.90.254
32.9592.7154490723564.23053840.22
34.322.6107437427084.8580697.60.365
34.6812.5844429718293.2372724.90.346
36.042.49396219793.5337574.40.29
36.6192.452400616342.9187042.50.195
38.9812.3087377614232.5137231.80.164
40.1212.2456336811892.1313624.10.448
40.622.2192327914492.6405245.30.475
Embodiment
Term used in the present invention has following implication.
" alkyl " represents the saturated monovalent hydrocarbon residue of straight or branched as used herein, the term.
C as used herein, the term
1-C
4alkyl represents the saturated monovalent hydrocarbon residue of the straight or branched containing 1 to 4 carbon atom, C
1-C
4the example of alkyl includes but not limited to: methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-and the tertiary butyl.
" alkoxyl group " represents-O-alkyl as used herein, the term, and wherein alkyl is as defined above, and as methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy, pentyloxy, hexyloxy, comprises their isomer." lower alkoxy " represents the alkoxyl group of " low alkyl group " group had as defined above as used in this article." C as used in this article
1-10" refer to-O-alkyl, wherein alkyl is C to alkoxyl group
1-10.
" haloalkyl " represents straight or branched alkyl as defined above as used herein, the term, and wherein 1,2,3 or more hydrogen atoms are optionally substituted by halogen.Term " low-grade halogenated alkyl " represents containing the straight or branched hydrocarbon residue of 1 to 6 carbon atom, and wherein 1,2,3 an or more hydrogen atom are optionally substituted by halogen.Example is 1-methyl fluoride, 1-chloromethyl, 1-brooethyl, 1-iodomethyl, difluoromethyl, trifluoromethyl, trichloromethyl, trisbromomethyl, three iodomethyls, 1-fluoro ethyl, 1-chloroethyl, 1-bromotrifluoromethane, 1-iodine ethyl, 2-fluoro ethyl, 2-chloroethyl, 2-bromotrifluoromethane, 2-iodine ethyl, 2,2-Dichloroethyl, 3-bromopropyl or 2,2,2-trifluoroethyl.
" aryl " represents monovalent monocyclic or bicyclic aromatic hydrocarbon groups as used herein, the term, preferred 6-10 unit aromatic ring system.Preferred aryl includes but not limited to phenyl, naphthyl, tolyl and xylyl.
" replacement or unsubstituted " expression can be replaced by one or more substituting group as used herein, the term, described substituting group is selected from: hydroxyl, cyano group, alkyl, alkoxyl group, thio group, elementary halogenated alkoxy, alkylthio, halogen, haloalkyl, alkyl sulphinyl, alkyl sulphonyl, halogen, amino, alkylamino, dialkyl amido, aminoalkyl group, alkylaminoalkyl group and dialkyl aminoalkyl, nitro, alkoxy carbonyl and formamyl, alkyl-carbamoyl, dialkyl carbamoyl, aryl-amino-carbonyl, alkyl-carbonyl-amino and aryl-amino-carbonyl, preferred C
1-C
4alkyl, alkoxy or halogen.
In a specific embodiment of the present invention, preparation formula IX compound method is provided, comprises the steps:
Q is p-toluenesulfonyl, to chlorobenzenesulfonyl etc.;
(1) formula I and formula II compound is made to generate formula III compound through acylation reaction
Wherein R is selected from C
1-C
4alkyl, phenyl or substituted-phenyl, benzyl or substituted benzyl, preferred sec.-propyl; Ar is selected from phenyl or substituted-phenyl, as p-methoxyphenyl etc.;
(2) formula III compound is made to react production IV compound with trioxymethylene generation hydroxy methyleneization under organic bases and titanium tetrachloride effect
Wherein R, Ar are as above-mentioned definition;
(3) formula IV compound and halogen or halide reagent is made to react production V compound under neutral or basic conditions, in applicable solvent
Wherein A is selected from Cl, Br or I, preferred Br, I; R, Ar are as above-mentioned definition;
(4a) formula V compound hydrolysis reaction production VI compound in alkaline condition and applicable solvent is made
Wherein A is as above-mentioned definition;
Or (4b) makes formula V compound react production VII compound under reductive agent existence condition, in applicable solvent
(5) formula VI compound is made to react production VII compound under Suitable reducing agent condition
Wherein A is as above-mentioned definition;
(6) formula VII compound and 1,2,3-triazole an alkali metal salt or 1,2,3-triazole is made to react production VIII compound under alkali and applicable reaction solvent and catalyzer exist
(7) formula VIII compound and QX sulfonyl compound is made to react production IX compound
Wherein Q is selected from p-toluenesulfonyl, to chlorobenzenesulfonyl etc.
The acylating reagent that wherein step (1) described acylation reaction is used can be selected from oxalyl chloride, pivaloyl chloride etc., thionyl chloride, POCl
3, PCl
3, PCl
5, preferred oxalyl chloride and pivaloyl chloride; Described alkali is selected from organometallic reagent as butyllithium, diisopropylamine lithium, or trimethylamine is as the mixture of triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine and Lithium chloride (anhydrous); Preferred employing oxalyl chloride, thionyl chloride is acylating agent, and alkali is the acylation condition of butyllithium and pivaloyl chloride and triethylamine Lithium chloride (anhydrous); Described solvent is selected from polar aprotic solvent as, one or more its mixed solvent in chlorinated solvents, ether solvent, preferably tetrahydrofuran (THF), methylene dichloride;
Step (2) described organic bases is selected from trimethylamine, as triethylamine, tri-tert amine, N-methylmorpholine, diisopropyl ethyl amine etc., and preferred triethylamine and diisopropyl ethyl amine; Described solvent is selected from aprotic solvent as chlorinated solvents, esters solvent, ether solvent, preferred methylene dichloride, 1,2-ethylene dichloride;
Step (3) described halide reagent comprises: halogen, preparing halogenated hydantoin, N-bromo-succinimide (NBS), N-N-iodosuccinimide (NIS), N-chlorosuccinimide (NCS) etc., preferred iodine, NIS bromine, NBS and C5H6Br2N2O2; Alkali is selected from alkali metal hydroxide, metal carbonate compound, metal carbonate hydride, preferred sodium bicarbonate; Described solvent is selected from polar aprotic solvent if tetrahydrofuran (THF), acetonitrile, ethyl acetate and protonic solvent are as water, one or more its mixed solvent in alcoholic solvent, the mixture of preferred tetrahydrofuran (THF) and water;
Step (4a) described alkali is selected from alkali metal hydroxide, metal carbonate compound, preferably sodium hydroxide; Described solvent is selected from the mixture of polar organic proton or non-protonic solvent and water, preferred tetrahydrofuran (THF) and water;
Step (4b) described reductive agent is selected from hydride reducer, preferred lithium borohydride; Solvent selected from methanol, ethanol, Virahol, tetrahydrofuran (THF), 2-methyltetrahydrofuran, methylene dichloride, ethyl acetate or more than one its mixed solvent.
Step (5) described reductive agent is selected from diisobutyl aluminium hydride, sodium borohydride, lithium borohydride, sodium borohydride/BF
3-ether, vitride, sodium borohydride/aluminum chloride or borine/aluminum chloride, sodium borohydride/iodine, 9-BNN, red aluminum solutions; Solvent is selected from organic dipolar aprotic solvent, as tetrahydrofuran (THF), toluene, methylene dichloride, and preferred tetrahydrofuran (THF), toluene;
Step (6) described alkali can be selected from metal hydride, metal alcoholate, metal carbonate compound, as NaH, KH, sodium alkoxide, Na
2cO
3, K
2cO
3; Described catalyzer comprises crown ether, as 15-hat-5,18-hat-6; Reaction solvent can be selected from dipolar aprotic solvent, as dimethyl sulfoxide (DMSO), DMF, N,N-dimethylacetamide, N-Methyl pyrrolidone.
A specific embodiments of the present invention provides the method for preparation formula IX compound, comprises the steps:
(1) formula V-a compound hydrolysis reaction production VI-a compound in alkaline condition and applicable solvent is made
(2) formula VI-a compound is made to react production VII-a compound under Suitable reducing agent condition
(3) formula VII-a compound and 1,2,3-triazole an alkali metal salt or 1,2,3-triazole is made to react production VIII compound under alkali and applicable reaction solvent and catalyzer exist
(4) formula VIII compound and QX sulfonyl compound is made to react production IX compound
Wherein Q is selected from tosyl group, to chlorobenzenesulfonyl etc.
Wherein step (1) described alkali is selected from alkali metal hydroxide, metal carbonate compound, preferably sodium hydroxide; Described solvent is selected from the mixture of polar organic proton or non-protonic solvent and water, preferred tetrahydrofuran (THF) and water;
Step (2) described reductive agent is selected from diisobutyl aluminium hydride, sodium borohydride, lithium borohydride, sodium borohydride/BF
3-ether, vitride, sodium borohydride/aluminum chloride or borine/aluminum chloride, sodium borohydride/iodine, 9-BNN, red aluminum solutions; Solvent is selected from organic dipolar aprotic solvent, as tetrahydrofuran (THF), and toluene, methylene dichloride, preferred tetrahydrofuran (THF), toluene;
Step (3) described alkali can be selected from metal hydride, metal alcoholate, metal carbonate compound, as NaH, KH, sodium alkoxide, Na
2cO
3, K
2cO
3; Described catalyzer comprises crown ether, as 15-hat-5,18-hat-6; Reaction solvent can be selected from dipolar aprotic solvent, as dimethyl sulfoxide (DMSO), DMF, N,N-dimethylacetamide, N-Methyl pyrrolidone.
Step (4) described alkali is selected from organic bases, as triethylamine, tributylamine, DMAP, N-methylmorpholine, diisopropylethylamine, and preferred diisopropylethylamine; Solvent is selected from alcoholic solvent, chlorinated solvent and varsol, preferred sherwood oil, Virahol and methylene dichloride.
The invention provides the method for preparation formula IV compound, comprise the following steps:
(1) formula I and formula II compound is made to generate formula III compound through acylation reaction
Wherein R, Ar are as above-mentioned definition;
(2) formula III compound is made to react production IV compound with trioxymethylene generation hydroxy methyleneization under organic bases and titanium tetrachloride effect.
Or from formula III compound as starting raw material synthesis type IV compound.
One embodiment of the invention provide the method for preparation formula VI compound, comprise the steps:
Wherein A is selected from Cl, Br or I, preferred Br, I;
(1) formula I and formula II compound is made to generate formula III compound through acylation reaction,
Wherein R, Ar are as above-mentioned definition;
(2) formula III compound trioxymethylene generation hydroxy methyleneization reaction production IV compound under organic bases and titanium tetrachloride effect is made
Wherein R, Ar are as above-mentioned definition;
(3) formula IV compound and halogen or halide reagent is made to react production V compound under neutral or basic conditions, in applicable solvent
Wherein A is as above-mentioned definition; R, Ar are as above-mentioned definition;
(4) formula V compound hydrolysis reaction production VI compound in alkaline condition and applicable solvent is made.
The invention provides intermediate formula III, formula IV compound and the application in synthesis type IX compound
Wherein R is selected from C
1-C
4alkyl, phenyl or substituted-phenyl, benzyl or substituted benzyl, preferred sec.-propyl; Ar is selected from phenyl or substituted-phenyl, as p-methoxyphenyl etc.
The invention provides intermediate formula III, formula IV compound is solid.
The invention provides intermediate formula V compound and the application in synthesis type IX compound and posaconazole
Wherein A is selected from Cl, Br or I, preferred Br, I; R is selected from C1-C4 alkyl, phenyl or substituted-phenyl, benzyl or substituted benzyl, preferred sec.-propyl; Ar is selected from phenyl or substituted-phenyl, as p-methoxyphenyl etc.
The invention provides intermediate formula VI-a compound and the application in synthesis type IX compound and posaconazole
Be further described with feature to various aspects of the present invention below.
Shortenings used herein is generally well-known to those skilled in the art, or can be understandable according to rudimentary knowledge.
The starting raw material adopted in the preparation of the compounds of this invention is known, that can prepare according to currently known methods or commercially available acquisition.
The invention still further relates to new intermediate and/or starting raw material.Particularly preferably with those the identical or similar reaction conditionss mentioned in embodiment and new intermediate.
Intermediate and end product can carry out aftertreatment and/or purifying according to conventional methods, and described ordinary method comprises and regulates pH, extraction, filtration, drying, concentrated, chromatography, grinding, crystallization etc.
In addition, the compounds of this invention can also be prepared by the alternative of various method known in the art or methods described herein.
The following example only for illustrating the present invention, limits the invention never in any form.
(1) preparation of formula III compound
2.5g (1.2mmol) formula I, add 3.45ml (2.5mmol) TEA, 25mlTHF, be chilled to-20 DEG C, drip 1.4ml (1.2mmol) pivaloyl chloride, maintain-20 DEG C of stirring reaction 2h, rise to room temperature, add 2.81g (1.0mmol) formula II and 0.5g (1.1mmol) Lithium chloride (anhydrous) successively, stirring at room temperature 24h, next day removes tetrahydrofuran (THF) under reduced pressure, residue adds water, use methyl tert-butyl ether extracting twice, combined ether extraction liquid, uses saturated NaHCO successively
3wash, 1NHCl washes, and washing, saturated NaCl washes, anhydrous Na
2sO
4drying, filter, filtrate evaporate to dryness, residue normal hexane recrystallization, obtains colourless crystallization 3.52 grams (63%).
(2) preparation of formula IV compound
By 1.5g (3.15mmol) formula III, after cryosel bath cooling, drip 3.3ml1NTiCl
4/ DCM solution, finishes, and stirs 15min, drips 0.46ml (3.3mmol), stirs 30min, then drips 0.3g (3.3mmol) trioxymethylene/1mlDCM solution, finish, and drips 3.3ml1NTiCl
4/ DCM solution, finishes, and in ice bath, stirring reaction 3h adds half saturated NH
4cl20ml stopped reaction, Rt stirs 15min, adds t-butyl methyl ether dilution, separates organic layer, wash successively with 1NHCl, saturated NaHCO
3wash, saturated NaCl washes, anhydrous Na
2sO
4drying, evaporated under reduced pressure, obtains off-white color solid 1.6g
1HNMR(400MHz，CDCl
3)δ7.20～7.52(m，11H)，6.72～6.68(m，1H)，6.64～6.60(t，J＝8Hz，1H)，6.64～6.52(m，1H)，5.42(s，1H)，4.86(s，1H)，4.73(s，1H)，3.90～3.96(m，1H)，3.82～3.86(dd，J＝10.8，4.4Hz，1H)，3.71～3.76(m，1H)，2.63～2.90(dd，j＝14，8.8Hz，1H)，2.43～2.48(dd，J＝14，5.2，1H)，1.92～2.0(m，1H)，0.88～0.90(d，J＝6.8，3H)，0.76～0.77(d，J＝6.8，3H)
Product; [α]
d 20; + 131.9 (CHCl
3, C0.48)
(3) preparation of formula V compound
250mg (0.5mmol) raw material is added 5mlTHF and 0.2mlH2O, after cryosel bath cooling, add 106mg (0.6mol) NBS, finish, finish stirring reaction 2.5h in ice bath, add the dilution of 20ml t-butyl methyl ether, wash with saturated sodium bisulfite successively, washing, saturated NaCl washes, anhydrous Na
2sO
4drying, filters, short column of silica gel purifying after filtrate is concentrated, and removing initial point impurity, PL/EtOAc wash-out, obtains white solid 240mg.
1HNMR(400MHz，CDCl
3)δ7.28～7.51(m，11H)，6.85～6.89(m，1H)，6.75～6.80(m，1H)，5.38(s，1H)，4.30(s，1H)，4.28(s，1H)，3.95～3.98(m，1H)，3.73～3.76(d，J＝11.2Hz，1H)，3.68～3.71d，J＝11.2Hz，1H)，2.50～2.55(m，1H)，2.34～2.40(m，1H)，1.98～2.04(m，1H)，0.88～0.90(d，J＝6.8，3H)，0.75～0.77(d，J＝6.8，3H)。
[α]
D 20；+112.2(CHCl
3，C0.505)
(4) preparation of formula VI compound
160mg raw material is dissolved in 2.5mlMeOH, 2.5mlTHF, add 0.43ml1MNaOH stirring at room temperature reaction 2h, remove solvent under reduced pressure, residue adds 15mlH
2o, filtered and recycled prothetic group, filtrate adjusts pH about to 2 with concentrated hydrochloric acid, uses EtOAc extracting twice, combining extraction liquid, washing, and Na2SO4 is dry, and filter, filtrate evaporate to dryness, short column of silica gel purifying, PL/EtOAc (1/1) wash-out, obtains oily matter 85mg, places solidification.
1HNMR(400MHz，CDCl
3)δ7.49～7.55(m，1H)，6.87～6.92(m，1H)，6.80～6.85(m，1H)，4.28～4.32(t，J＝8.8Hz，1H)，4.16～4.21(t，J＝8.8Hz，1H)，3.82～3.85(d，J＝10.8，Hz，1H)，3.77～3.80(d，J＝10.8，Hz，1H)，3.11～3.15(m，1H)，2.74～2.79(m，1H)，2.62～2.67(m，1H)
(5) preparation of formula VII compound
Raw material is dissolved in 3mlTHF, and ice bath cools, and adds 0.05mlBH3.Sme2, finish, in ice bath, stirring reaction 15min, stirring at room temperature 35min add methyl alcohol stopped reaction, remove solvent under reduced pressure, residue adds t-butyl methyl ether, and saturated NaHCO3 washes, washing, anhydrous Na 2SO4 is dry, filters, short column of silica gel purifying after filtrate is concentrated,, PL/EtOAc (2/1) wash-out, obtains oily matter
1HNMR(400MHz，CDCl
3)δ7.51～7.57(m，1H)，6.87～6.90(m，1H)，6.78～6.80(m，1H)，4.09～4.11(dd，J＝7.0，4.2Hz，1H)，3.87～3.91(dd，J＝7.0，4.2Hz，1H)，3.79(s，2H)，3.70～3.72(m，2H)，2.42～2.51(m，2H)，2.15～2.19(m，1H)，1.49(brs，1H)[α]
D 20；+2.3(CHCl
3，C0.98)
(6) preparation of formula VIII compound
165mg raw material is added 2.5mlDMSO to dissolve, add 290mg triazole sodium, 50mgNaI and 1d15-hat-5, in 80 ~ 90 DEG C of oil baths, heated and stirred reaction 24h, methylate-THF dilute, wash three times, it is dry that saturated NaCl washes anhydrous Na 2SO4, filters, short column of silica gel purifying after filtrate is concentrated, DCM ~ DCM/MeOH (10/1) wash-out, obtains 100mg.HR-MS (ESI) C14H16F2N3O2 (M+H)+: calculated value 296.1205 measured value 296.1200
(7) preparation of formula IX compound
310mg (1.05mmol) raw material is added 5mlDCM to dissolve, add 0.36ml (2.5mmol), Et3N and 64mgDMAP, ice bath cools, and adds 220mg (1.1mmol) TsCl, finish, ice bath reaction 30min, dislocation room temperature (about 15 DEG C) stirring reaction spends the night, and reaction solution adds DCM dilution, wash with 1NHCl successively, saturated NaHCO3 washes, washing, and Na2SO4 is dry; Filter, filtrate evaporate to dryness, obtains light yellow gum thing (entrained solids) 370mg, upper silicagel column, Hexane/Acetone (4/1 ~ 2/1) wash-out, obtains Cis-product 210mg (white solid) Cis-product; [α]
d 20=-37.4 (CHCl
3, C1.0)
1HNMR(400MHz，CDCl
3)δ8.02(s，1H)，7.74～7.76(m，3H)，7.35～7.37(d，2H)，7.3(m，1H)，6.80～6.83(m，2H)，4.43～4.55(Abq，2H)，3.96～4.00(m，1H)，3.82～3.86(m，1H)，3.66～3.71(m，1H)，3.55～3.58(m，1H)2.48～2.51(m，2H)，2.47(s，3H)，1.89～1.92(m，1H)
HR-MS (ESI) C21H22F2N3O4S (M+H)+: calculated value 450.1293 measured value 450.2414
(8) preparation of formula B compound
Add 10g formula A and 76mLDMSO in room temperature downhill reaction bottle, stir clearly molten, then add the alkali lye prepared by 1.4g sodium hydroxide and 6g water in advance, stir 1h, then add 10g formula IX, and be warmed up to 38 DEG C of reaction 16h, after question response is complete, be warmed up to 45 DEG C and drip 6mL water, stir 30-60min, then add 154mL water, stir 1h, suction filtration, solid 4 × 50mL purified water drip washing obtains wet product.
Wet product and 60mL are joined in reaction flask, be warmed up to 65 DEG C of stirrings, until molten clear after add 1.5g gac, stir 15min, press filtration while hot, and wash with the aqueous ethanolic solution of 15mL90%, then filtrate is warmed up to 65 DEG C of stirrings, until molten clear after cool to 40-45 DEG C of insulation crystallization 1h, then cool to 0-5 DEG C of insulation crystallization 1h, suction filtration, the aqueous ethanolic solution drip washing of 5mL50% first used by solid, use the drip washing of 4 × 50mL purified water again, collect solid, put it into the dry 16h of 50-55 DEG C of convection oven and obtain 13.2g.
(9) synthesis of posaconazole
10g formula B is added in room temperature downhill reaction bottle, 100mL methyl alcohol and 10g refine hydrochloric acid, the Pd/C of 1g5% is added after stirring 1h, then hydrogen is passed into, and temperature is to 40 DEG C of stirring reaction 10-16h, the completely rear suction filtration of question response, solid 10mL methanol wash, filtrate is warmed up to 45 DEG C, and drip the pH to 7-8 of the alkali lye regulator solution be made into by 2.7g sodium hydroxide and 17g water, then 60-65 DEG C is warmed up to, and slowly drip 60mL purified water, 45 DEG C of insulation crystallization 1h are cooled to after dripping off, cool to 15-20 DEG C of insulation crystallization 1h again, suction filtration, the methanol aqueous solution drip washing of 5mL50% first used by solid, use the drip washing of 4 × 50mL purified water again, collect solid, put it into the dry 16h of 50-55 DEG C of convection oven and obtain 9.4g.
In order to clear and understandable object, explanation and embodiment describe in detail foregoing invention by way of example.Can carry out changing and revising in the scope of subsidiary technical scheme, this be clearly to one skilled in the art.Therefore, the specification sheets being appreciated that above be intended to for illustration of instead of for restriction.Therefore, scope of the present invention should not determined with reference to above-mentioned specification sheets, and should determine with reference to the determined four corner of doctrine of equivalents that appended technical scheme and these technical schemes are enjoyed below.
Claims (45)
1. the compound of formula III,
Wherein,
R is selected from C
1-C
4alkyl, replacement or unsubstituted phenyl, replacement or unsubstituted benzyl, preferred sec.-propyl;
Two Ar can be identical or different, is selected from replacement or unsubstituted aryl independently of one another, preferably replace or unsubstituted phenyl, as p-methoxyphenyl,
Described compound is preferably solid form.
2. the compound of formula IV,
Wherein,
R and Ar is as defined above,
Described compound is preferably solid form.
3. the compound of formula V,
Wherein,
R and Ar is as defined above; And
A is Br, Cl or I, preferred Br,
Described compound is preferably solid form.
4. the compound of formula VI,
Wherein,
A is selected from Cl or Br, preferred Br,
Described compound is preferably solid form.
5. the compound of formula VII,
Wherein,
A is selected from Cl or Br, preferred Br,
Described compound is preferably solid form.
6. prepare a method for the compound of formula III,
Described method comprises:
Make the compound of formula I and the compound generation acylation reaction of formula II,
Wherein,
R and Ar is as defined above.
7. method according to claim 6, wherein:
Described acylation reaction adopts one or more acylating reagents be selected from the following: oxalyl chloride, pivaloyl chloride, thionyl chloride, POCl
3, PCl
3, PCl
5, preferred oxalyl chloride, thionyl chloride or pivaloyl chloride; And/or
Described acylation reaction is carried out under the existence being selected from one or more alkali in the following: organometallic reagent is as butyllithium, diisopropylamine lithium, or the mixture of trimethylamine (as triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine) and Lithium chloride (anhydrous); And/or
Described acylation reaction preferably at butyllithium, or is carried out under the existence of the mixture of pivaloyl chloride and triethylamine and Lithium chloride (anhydrous); And/or
Described acylation reaction is carried out under the existence of polar aprotic solvent, as chlorinated solvents, ether solvent, and the one in preferred tetrahydrofuran (THF), methylene dichloride or its mixture.
8. a method for the compound of preparation formula IV,
Described method comprises:
The compound trioxymethylene of formula III is carried out hydroxy methylene,
Wherein,
R and Ar is as defined above.
9. method according to claim 8, wherein:
Described hydroxy methylene carries out under organic bases and titanium tetrachloride effect; And/or
Described organic bases be selected from the following one or more: trimethylamine, as triethylamine, tri-tert amine, N-methylmorpholine, diisopropyl ethyl amine, preferred triethylamine or diisopropyl ethyl amine; And/or
Described hydroxy methylene carries out in by one or more solvents be selected from group that the following forms: aprotic solvent as chlorinated solvents, esters solvent, ether solvent, preferred methylene dichloride, 1,2-ethylene dichloride.
10. a method for the compound of preparation formula V,
Described method comprises:
The compound of formula IV and halide reagent are reacted,
Wherein,
R and Ar is as defined above;
A is Br, Cl or I.
11. methods according to claim 10, wherein:
Described reaction is carried out under neutral or basic conditions; And/or
Described halide reagent comprise be selected from the following one or more: halogen, preparing halogenated hydantoin, N-bromo-succinimide (NBS), N-N-iodosuccinimide (NIS), N-chlorosuccinimide (NCS), preferred iodine, NIS bromine, NBS or C5H6Br2N2O2; And/or
Described reaction is carried out under the existence being selected from one or more the alkali in the following: alkali metal hydroxide, metal carbonate compound, metal carbonate hydride, preferred sodium bicarbonate; And/or
Described reaction is carried out being selected from one or more solvents in the group be made up of the following: polar aprotic solvent if tetrahydrofuran (THF), acetonitrile, ethyl acetate and protonic solvent are as water, alcoholic solvent, the mixture of preferred tetrahydrofuran (THF) and water.
The method of the compound of 12. 1 kinds of preparation formula VI,
Described method comprises:
By the compound hydrolysis of formula V,
Wherein,
R and Ar is as defined above;
A is Br, Cl or I.
13. methods according to claim 12, wherein said hydrolysis is carried out in the basic conditions.
14. methods according to claim 12, wherein said hydrolysis is carried out under the existence being selected from one or more alkali in the following: alkali metal hydroxide, metal carbonate compound, preferred sodium hydroxide.
15. methods according to claim 12, wherein said hydrolysis is carried out being selected from one or more solvents in the group be made up of the following: the mixture of polar organic proton or non-protonic solvent and water, preferred tetrahydrofuran (THF) and water.
The method of the compound of 16. 1 kinds of preparation formula VII,
Described method comprises:
The compound of formula V is reduced,
Wherein,
R and Ar is as defined above;
A is Br, Cl or I.
17. methods according to claim 16, wherein:
Described reduction hydrogenation uses one or more the reductive agent be selected from the following: hydride reducer, preferred lithium borohydride; And/or
Described reduction is carried out in by one or more solvents formed be selected from the following: methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), 2-methyltetrahydrofuran, methylene dichloride and ethyl acetate.
The method of the compound of 18. 1 kinds of preparation formula VII,
Described method comprises:
The compound of formula VI is reduced,
Wherein,
A is Br or Cl.
19. methods according to claim 18, wherein said reduction uses one or more reductive agents be selected from the following: diisobutyl aluminium hydride, sodium borohydride, lithium borohydride, sodium borohydride/BF
3-ether, vitride, sodium borohydride/aluminum chloride or borine/aluminum chloride, sodium borohydride/iodine, red aluminum solutions.
20. methods according to claim 18, wherein said reduction is carried out being selected from one or more solvents in the group be made up of the following: organic dipolar aprotic solvent, as tetrahydrofuran (THF), toluene, methylene dichloride, preferred tetrahydrofuran (THF), toluene.
The method of the compound of 21. 1 kinds of preparation formula IX,
Said method comprising the steps of:
G) compound of formula VII and 1,2,3-triazole an alkali metal salt or 1,2,3-triazole is made to react,
The compound of production VIII,
F) by the compound sulfonylation of formula VIII;
Wherein,
Q is selected from replacement or unsubstituted benzenesulfonyl, preferred p-toluenesulfonyl, to chlorobenzenesulfonyl;
A is Br;
Described method also optionally comprises the following steps:
According to claim 16 to the compound of the method preparation formula VII described in any one in 20.
22. methods according to claim 21, wherein:
Step g) carry out under the existence being selected from one or more alkali in the following: metal hydride, metal alcoholate, metal carbonate compound, as NaH, KH, sodium alkoxide, Na
2cO
3, K
2cO
3; And/or
Described step g) when A is Cl, Br, carry out under the existence being selected from one or more catalyzer in the following: crown ether, as 15-hat-5,18-hat-6, tetrabutylammonium iodide, catalytic amount KI, NaI; And/or
Described step g) carry out being selected from one or more solvents in the group be made up of the following: dipolar aprotic solvent, as dimethyl sulfoxide (DMSO), DMF, N,N-dimethylacetamide, N-Methyl pyrrolidone.
23. methods according to claim 21, wherein said sulfonylation uses QX as sulfonylation agent,
Wherein,
Q is selected from replacement or unsubstituted benzenesulfonyl, preferred p-toluenesulfonyl, to chlorobenzenesulfonyl;
X is Br, Cl or I; And/or
Described sulfonylation carries out under the existence being selected from one or more alkali in the following: organic bases, as triethylamine, tributylamine, DMAP, N-methylmorpholine, diisopropylethylamine, and preferred diisopropylethylamine; And/or
Described sulfonylation carries out being selected from one or more solvents in the group be made up of the following: chlorinated solvent and varsol, preferred methylene dichloride, toluene, tetrahydrofuran (THF).
24. prepare a method for the composition of the compound of contained IX,
Said method comprising the steps of: from formula VI compound
G) compound of formula VII and 1,2,3-triazole an alkali metal salt or 1,2,3-triazole is made to react,
Wherein A is Br, Cl or I,
With the compound of production VIII,
F) by the compound sulfonylation of formula VIII;
G) recrystallization;
Obtain
The compound of contained IX, and the compound of contained X,
Wherein, relative to the total mass of composition, the mass percent of the compound of described formula IX is 95% to 100%, and the mass percent of described formula X is 0% to 5.0%
Described composition is preferably solid form.
25. methods according to claim 24, wherein
Step g) carry out under the existence being selected from one or more alkali in the following: metal hydride, metal alcoholate, metal carbonate compound, as NaH, KH, sodium alkoxide, Na
2cO
3, K
2cO
3; And/or
A is Cl or Br, described step g) carry out under the existence being selected from one or more catalyzer in the following: crown ether, as 15-hat-5,18-hat-6, tetrabutylammonium iodide, catalytic amount KI, NaI; And/or
Described step g) carry out in by one or more solvents formed be selected from the following: dipolar aprotic solvent, as dimethyl sulfoxide (DMSO), DMF, N,N-dimethylacetamide, N-Methyl pyrrolidone.
26. methods according to claim 24, wherein:
Described sulfonylation uses QX as sulfonylation agent,
Wherein,
Q is selected from replacement or unsubstituted benzenesulfonyl, preferred p-toluenesulfonyl, to chlorobenzenesulfonyl;
X is Br, Cl or I; And/or
Described sulfonylation carries out under the existence being selected from one or more alkali in the following: organic bases, as triethylamine, tributylamine, DMAP, N-methylmorpholine, diisopropylethylamine, and preferred diisopropylethylamine; And/or
Described sulfonylation carries out in by one or more solvents formed be selected from the following: chlorinated solvent and varsol, preferred methylene dichloride, toluene, tetrahydrofuran (THF).
Method described in 27. claims 8 or 9, the compound of wherein said formula III is by the method preparation described in claim 6 or 7.
Method described in 28. claims 10 or 11, the compound of wherein said formula IV is by the preparation of the method described in any one in claim 8 to 9 and 27.
Method described in any one in 29. claims 12 to 15, the compound of wherein said formula V is by the preparation of the method described in any one in claim 10 to 11 and 28.
Method described in any one in 30. claims 16 to 17, the compound of wherein said formula V is by the preparation of the method described in any one in claim 10 to 11 and 28.
Method described in any one in 31. claims 18 to 20, the compound of wherein said formula VI is by the preparation of the method described in any one in claim 12 to 15 and 29.
32. compounds according to claim 3, described compound is by the preparation of the method described in any one in claim 10 to 11 and 28.
33. compounds according to claim 4, described compound is by the preparation of the method described in any one in claim 12 to 15 and 29.
The purposes of compound described in any one in 34. claims 1 to 5 and 32 to 33 in the synthesis of posaconazole.
Compound described in any one in 35. claims 1 to 5 and 32 to 33, described compound is used for the synthesis of posaconazole.
36. 1 kinds of methods of synthesizing posaconazole, described method comprises the step being prepared compound according to claim 1 by the method described in claim 6 or 7.
37. 1 kinds of methods of synthesizing posaconazole, described method comprises the step being prepared compound according to claim 2 by the method described in any one in claim 8 to 9 and 27.
38. 1 kinds of methods of synthesizing posaconazole, described method comprises the step being prepared compound according to claim 3 by the method described in any one in claim 10 to 11 and 28.
39. 1 kinds of methods of synthesizing posaconazole, described method comprises the step being prepared compound according to claim 4 by the method described in any one in claim 12 to 15 and 29.
40. 1 kinds of methods of synthesizing posaconazole, described method comprises the step being prepared compound according to claim 5 by the method described in any one in claim 16 to 20 and 30 to 31.
41. 1 kinds of methods of synthesizing posaconazole, described method comprises the step of the compound by the method preparation formula IX described in any one in claim 21 to 23,
Wherein,
Q is selected from replacement or unsubstituted benzenesulfonyl, preferred p-toluenesulfonyl, to chlorobenzenesulfonyl.
The method of the synthesis posaconazole described in any one in 42. claims 36 to 41, said method comprising the steps of:
The compound of formula IX and the compound of formula A are reacted,
Wherein,
Q is selected from replacement or unsubstituted benzenesulfonyl, preferred p-toluenesulfonyl, to chlorobenzenesulfonyl;
The compound of production B,
And be posaconazole by the compound hydrolysis of formula B.
The N crystal form of the compound of 43. 1 kinds of formula B,
Described N crystal form has XRD spectra as shown in Figure 1.
The N crystal form of the compound of 44. formula B according to claim 43, the N crystal form of the compound of described formula B is by the preparation of the method described in any one in claim 36 to 42.
The purposes of the method described in any one in compound described in any one in 45. claim 1-5,32-33 and 35 and/or claim 6-31 and 36-42 in the N crystal form of the compound of preparation formula B according to claim 43.
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