CN1066136C - Intermediate of pyrido-benzoxazine derivative and prepn. method - Google Patents

Intermediate of pyrido-benzoxazine derivative and prepn. method Download PDF

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CN1066136C
CN1066136C CN94107432A CN94107432A CN1066136C CN 1066136 C CN1066136 C CN 1066136C CN 94107432 A CN94107432 A CN 94107432A CN 94107432 A CN94107432 A CN 94107432A CN 1066136 C CN1066136 C CN 1066136C
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CN1115315A (en
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谢伦嘉
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CHINA MEDICINE RESEARCH AND DEVELOPMENT CENTRE
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Abstract

The present invention discloses a novel n-isopropylphenylamine derivant as the following chemical formula (I), wherein X1, X2 and X3 can be identical or different, and respectively represent halogen atoms, or one of the X1, the X2 and the X3 is a hydrogen atom, and the rest is the halogen atoms; Y is a halogen atom; a is a-CH2OR base, and R is the hydrogen atom or a hydroxy protecting base, or the A is a-COOR base; R <3> denotes the hydrogen atom and a protecting base of an alkyl with 1 to 6 carbon or carboxyl; one of R <1> and R <2> is an alkyl with 1 to 4 carbon, and the other is the hydrogen atom; Z is the hydrogen atom and a-CH-C(COOR<4>)2 base; the R <4> is an alkyl with 1 to 6 carbon, or the Z is a-SO2R<5> base or a-COR<5> base; the R <5> is hydrocarbyl or substituent hydrocarbyl. The present invention simultaneously discloses a method for preparing a compound in the chemical formula (I) and a method for preparing a benzoxazine derivative using the compound in the chemical formula (I).

Description

Intermediate of pyrido-benzoxazine derivative and preparation method thereof
The present invention relates to racemization and optical activity N-isopropyl benzene sulfonamide derivatives and preparation method thereof, relate to application racemization or optical activity N-isopropyl benzene sulfonamide derivatives and prepare racemization or optical activity pyrido-benzoxazine derivative important intermediate 3,4-two hydrogen benzo-oxazine derivatives.The present invention be more particularly directed to the optical activity Ofloxacine USP 23, as Levofloxacin, and the useful intermediates of analogue and preparation method thereof.
European patent EP 47005 discloses the Ofloxacine USP 23 (oflox-acin) of following chemical formula (IX) as efficient, wide spectrum synthetic antibacterial drug.Ofloxacine USP 23 is in listing of many countries and clinical use.
Figure 9410743200041
Above-mentioned bibliographical information, 7,8-two fluoro-3,4-dihydro-3 methyl-2H-[1,4] benzoxazine is the intermediate of synthetic Ofloxacine USP 23.
Day disclosure special permission 83-210092 report, 6,8-two chloro-7 fluoro-3-methyl-3,4-dihydro-2H-[1,4] benzoxazine also is the intermediate of synthetic Ofloxacine USP 23.
European patent EP 206283A2 discloses the Levofloxacin (levofloxacin or (S)-(-)-ofloxacin) of following chemical formula (X) again.It is than the antibiotic work of Ofloxacine USP 23 The property strong, toxicity is low and water-soluble big.At present, Levofloxacin is gone on the market in Japan.
(S)-(-)-7,8-two fluoro-3,4-dihydro-3-methyl-2H-[1,4] benzoxazine is the useful important intermediate of the optical activity pyrido-benzoxazine derivative (pyridobenzoxazine derivatives) of synthetic Levofloxacin and other anti-microbial activity.
Preparation (S)-(-)-7,8-two fluoro-3,4-dihydro-3-methyl-2H-[1,4] method of benzoxazine has,
1, Split Method: EP206283 for example, EP304684; Day disclosure special permission 90-31695.These methods are by splitting 7,8-two fluoro-3,4-dihydro-3-methyl-2H-[1,4] benzoxazine obtains S-(-) isomer, but yield is not higher than 50%, and its by product R-(+) isomer needs racemization, complicated operation.7,8-two fluoro-3,4-dihydro-3-methyl-2H-[1,4] preparation of benzoxazine need use sublimability and contaminative strong 2,3-two fluoro-6-nitrophenols intermediates and tearing property be strong-monochloroacetone.
2, asymmetric synthesis method: EP273399 report is by asymmetric reduction 7,8-two fluoro-3-methyl-2H-[1,4] benzoxazine makes corresponding (S)-(-) isomer.This method needs valuable chiral reduction reagent, and also uses 2,3-two fluoro-6-nitrophenolss and-monochloroacetone.
3, synthesis method: the EP322815 of chirality unit, the method of EP368410 and day disclosure special permission 90-218648 all is and chiral reagent generation etherification reaction, through 3,4-two fluoro-2-[(R)-and 2-hydroxyl propoxy-] the synthetic S-(-)-7 of oil of mirbane intermediate, 8-two fluoro-3,4-dihydro-3-methyl-2H-[1,4] benzoxazines.Several intermediates of these literature methods are oily matter, wherein 3,4-two fluoro-2-[(R)-2-hydroxyl propoxy-] functional group position isomerism, separation and purification difficulty easily take place in oil of mirbane under acid-base function.
4, biotransformation method: the method that day disclosure is speciallyyed permit 93-68577 to be provided is with micro-reduction 2-acetone oxygen base-3, the 4-difluoro nitrobenzene generates 3,4-two fluoro-2-[(R)-2-hydroxyl propoxy-] the oil of mirbane intermediate, there is easy isomerization equally in this intermediate, the separation and purification difficult problem.And 2-acetone oxygen base-3,4-difluoro nitrobenzene are by 2, and 3-two fluoro-6-nitrophenolss and Mono Chloro acetone prepare.
In order to solve the problem that above-mentioned literature method exists, the invention provides the racemization of following chemical formula I or optically active compound and preparation method thereof, and the racemization of the conduct of using preparation chemical formula (V) or the intermediate of optically active compound, particularly as preparation (S)-(-)-7,8-two fluoro-3,4-dihydro-3-methyl-2H-[1, the intermediate of 4] benzoxazines
X wherein 1, X 2And X 3Can be identical or different, each represents halogen atom or X 1, X 2, X 3One of them is a hydrogen atom, and all the other are halogen atom, and Y is a halogen atom, and A is-CH 2OR base (R is the protecting group of hydrogen atom or hydroxyl) or-COOR 3Base (R 3Be hydrogen atom, the alkyl of 1 to 6 carbon or the protecting group of carboxyl), R 1And R 2Both one of for containing the alkyl of 1 to 4 carbon, another is a hydrogen atom, Z is a hydrogen atom ,-CH-C (COOR 4) 2Base (R 4Be the alkyl of 1 to 6 carbon) ,-SO 2R 5The base or-COR 5Base, (R 5Be alkyl or substituted hydrocarbon radical), Z specifically :-CH-C (COOEt) 2, p-toluenesulfonyl, benzenesulfonyl, methylsulfonyl, phenacyl alkylsulfonyl, trifluoromethyl sulfonyl, benzoyl, carbobenzoxy, formyl radical, ethanoyl, trifluoroacetyl group etc.Preferably p-toluenesulfonyl or benzoyl.
The racemization of chemical formula (V) or optically active compound can be made through figure below reactions steps by the racemization or the optically active compound of chemical formula I:
In the above-mentioned chemical formula I, if A is-CH 2The OR base; wherein R is that (comprise the aliphatic radical such as the tertiary butyl, acyl group is formyl radical for example, ethanoyl for the general protecting group of hydroxyl; trifluoroacetyl group; benzene oxygen ethanoyl, ethers such as THP trtrahydropyranyl, methoxyl methyl; the 1-ethoxyethyl; virtue aliphatic radical such as benzyl are to methoxybenzyl, to nitrobenzyl or trityl etc.Benzyl preferably.), then (I) formula compound needs deprotection base R to make the compound of chemical formula (VII).
If A is-COOR 3Base (R 3Be hydrogen atom, the alkyl of 1 to 6 carbon or the protecting group of carboxyl.Preferably methyl or ethyl), the compound of chemical formula I need be reduced into the compound of chemical formula (VII).
By the compound and the intermediate (I) thereof of the prepared chemical formula of the inventive method (V), (VII) can be applied to prepare racemization or optical activity pyrido benzimidazole dihydrochloride derivative, particularly Levofloxacin.
The compound of following chemical formula (VII),
X wherein 1, X 2, X 3, Y, R 1And R 2Have above-mentioned implication, Z represents hydrogen atom ,-CH-C (COOR 4) 2Base (R 4Be the alkyl of 1 to 6 carbon) ,-SO 2R 5The base or-COR 5Base (R 5Be alkyl or substituted hydrocarbon radical), can by chemical formula the halogenated nitrobenzene derivative of (XI),
Figure 9410743200082
X wherein 1, X 2, X 3Have implication as mentioned above with Y, the several reactions steps by following reaction synoptic diagram (A) obtain: a) nitro-reduction reaction, b) amido protecting, c) N-alkylation reaction, d) (d1) dehydroxylation protecting group or (d2) ester or acid are reduced into the primary alconol reaction.
Reaction synoptic diagram (A)
X wherein 1, X 2, X 3, Y, Z, R 1, R 2And R 3Have implication as mentioned above, R is a hydroxyl protecting group, and C is-CH=C (COOR 4) 2Base (R 4Alkyl for 1-6 carbon) ,-SO 2R 5The base or-COR 5Base, B is-SO 2R 5Base (R 5Be alkyl or substituted hydrocarbon radical).
Describe each the step reaction in the reaction synoptic diagram (A) below in detail:
Reactions steps is nitro-reduction reaction a)
Nitro in the compound of chemical formula (XI) uses the catalyst hydro-reduction such as Raney nickel, palladium charcoal, platinum oxide to become amino, thereby obtains the compound of chemical formula (XII).Perhaps use such as the metal-sour restoring system of iron powder with hydrochloric acid nitroreduction is become amino.Reaction solvent comprises lower alcohol such as methyl alcohol, ethanol and propyl alcohol.Temperature of reaction is in the boiling spread of room temperature to solvent.Catalytic hydrogenation can be carried out under condition of high voltage at normal pressure.Generally at synthesis under normal pressure.
Reactions steps b): amido protecting
Amino available-SO in the compound of chemical formula (XII) 2R 5Base ,-COR 5Base (R 5Be alkyl or substituted hydrocarbon radical) or-CH=C (COOR 4) 2Base (R 4Be the alkyl of 1 to 6 carbon) protection.Use R 5SO 2Cl, R 5COCl (or other acylating agent such as active ester, acid anhydrides, acid add DCC etc.) carries out acylation reaction to the compound of chemical formula (XII).Perhaps chemical formula is Q-CH=C (COOR 4) 2Compound, Q representation alkoxy wherein, halogen or-N (R 4) 2Compound generation condensation reaction with chemical formula (XII).Thereby obtain the compound of chemical formula III.
Acylation reaction is preferably in alkali and exists down, uses the R such as Tosyl chloride 5SO 2Cl or the R such as Benzoyl chloride 5COCl is to the compound acylation of chemical formula (XII).Alkali used herein comprises such as triethylamine.Tri-n-butylamine, N, N-diisopropylethylamine and so on tertiary amine and, the heterocyclic bases of N-methylmorpholine and so on such as pyridine, lutidine.
Reacting suitable solvent is aprotic solvent, comprises ethers such as the tetrahydrochysene furan food in one's mouth, 1, and 2-glycol dimethyl ether etc. and halo alkanes such as methylene dichloride, chloroform, 1,2-ethylene dichloride etc.
Temperature of reaction at 0 ℃ between the solvent boiling point.Be preferably between 0 ℃ to 50 ℃.
Reactions steps c): the N-alkylation reaction
(wherein C is-SO the compound of chemistry formula III 2R 5The base or-COR 5Base, R 5Be alkyl or substituted hydrocarbon radical) with the racemization of following chemical formula (X III) or have optically active compound,
R wherein 1And R 2Both one of for containing the alkyl of 1 to 4 carbon, another be a hydrogen atom, R is the protecting group of hydroxyl, X comprises optional mesyloxy for reacting leavings group, fluoroform 1 sulfonyloxy, phenylsulfonyloxy, tolysulfonyl oxygen base, halogen, chemical formula are Ph 3The triphenyl phosphine oxygen base of PO-etc.,
The N-alkylation reaction takes place to be generated the racemization of chemical formula VI or have optically active N-isopropyl benzene sulfonamide derivatives,
The perhaps racemization of (III) formula compound and following chemical formula (X IV) or have optically active propanoic derivatives,
R wherein 1, R 2Have the above implication, R with X 3It is for example benzyl of the suitable protecting group of the alkyl of 1 to 6 carbon or carboxyl.
In the presence of alkali and phase-transfer catalyst, the N-alkylation reaction takes place, generate the racemization of chemical formula (VIII) or have optically active compound.
Alkali used herein refers to mineral alkali or organic bases.Mineral alkali comprises alkali hydroxide metal such as lithium hydroxide, sodium hydroxide, potassium hydroxide comprises carbonic acid basic metal such as Quilonum Retard, yellow soda ash, salt of wormwood, organic bases comprise tertiary amine such as triethylamine, tri-n-butylamine, N, the N-diisopropylethylamine comprises quaternary ammonium hydroxide such as tetraethylammonium hydroxide, hydroxide dimethyl decyl benzyl ammonium.Hydroxide trimethylammonium ammonium in the last of the ten Heavenly stems comprises sodium alkoxide or potassium alcoholate such as sodium methylate, sodium ethylate, sodium isopropylate, sodium tert-butoxide etc.
Phase-transfer catalyst used herein refers to the crown ether such as hexaoxacyclooctadecane-6, De quaternary alkylphosphonium salt and quaternary ammonium salt such as bromination Shi six alkyl San Ding Ji phosphonium salts.Quaternary ammonium salt comprises 4-n-butyl ammonium hydrogen sulfate, bromination tetra-n-butyl ammonium, chlorination triethyl benzyl ammonium, bromination dodecyl dimethyl benzyl ammonium, cetyl trimethylammonium bromide, Alaqual336 etc.
The solvent that the N-alkylation reaction uses comprises hydrocarbon such as benzene, and toluene etc. comprise ether such as the tetrahydrochysene furan food in one's mouth, dioxane, 1,2-glycol dimethyl ether etc. comprise acid amides and N, dinethylformamide etc., comprise aprotic polar solvent such as dimethyl sulfoxide (DMSO) etc., comprise alkyl chloride such as methylene dichloride, chloroform, tetracol phenixin, 1, the 1-ethylene dichloride, 1,2-ethylene dichloride, 1,1,2,2-tetrachloroethane etc.
Temperature of reaction in room temperature between the solvent boiling point.
(wherein C is-CH=C (COOR the compound of chemistry formula III 4) 2Base, R 4Be the alkyl of 1 to 6 carbon) and the compound (wherein X is a hydroxyl) of chemical formula (X III) or the compound (wherein X is a hydroxyl) of chemical formula (X IV), at 0-50 ℃, and feeding such as ether, tetrahydrochysene furan and 1, (see O.Mitsunobn with the doubly molar Mitsnnobn reagent of 1-1.5 in the solvent of 2-glycol dimethyl ether and so on, Synthesis, 1,28 (1981)) handle, thereby the N-alkylation reaction takes place, and (wherein C is-CH=C (COOR to generate the compound of chemical formula VI 4) 2Base) or generate the compound of chemical formula (VIII) (wherein C is-CH-C (COOR 4) 2Base, (R 4Be the alkyl of 1 to 6 carbon).
The compound of chemical formula (X IV) can be made by 2-hydroxycarboxylic acid ester derivative.For example produce from lactate.The compound of chemical formula (X III) can be by 1, and 2-alkyl diol derivative makes.1,2-alkyl diol derivative is to be obtained or obtained by 1-hydroxyketone-2 derivative such as the reduction of 1-pyruvic alcohol by the reduction of 2-hydroxycarboxylic acid esters.2-hydroxycarboxylic acid ester derivative and 1, the 2-position hydroxyl in the 2-alkyl diol derivative can for example be converted into the leavings group that replaces sulfonyloxy or halogen and so on replacement SULPHURYL CHLORIDE or sulfur oxychloride reaction by currently known methods in the presence of alkali.
2-hydroxycarboxylic acid or its ester comprise optically pure isomer or two kinds of enantiomeric mixture such as raceme, can be bought by market obtain.1 of optical purity or two kinds of enantiomeric mixture, 2-alkyl diol derivative is perhaps prepared from 1-hydroxyketone-2 derivative by asymmetric reduction or biological enzyme reduction method by corresponding 2-hydroxycarboxylic acid esters of reduction or acid preparation.
After it should be noted that the compound of the compound of chemical formula III and chemical formula (X III) or with the compound of chemical formula (X IV) the N-alkylation reaction taking place, the configuration generation Walden (Walden) of 2 asymmetric carbons of chiral centre transforms in the compound of the compound of chemical formula (X III) or chemical formula (X IV).The for example compound of (2R)-2-tolysulfonyl oxygen base ethyl propionate and chemical formula III reaction, thus corresponding (S) configuration chemical formula (VIII) compound (R wherein generated 1=Me, R 2=H, R 3=El)
Reactions steps d), the compound of preparation chemical formula (VII)
(d1): the dehydroxylation protecting group
Hydroxyl protecting group R in the compound of chemistry formula VI changes the H atom into by usual method deprotection base.For example R is that the protecting group of benzyl can be with palladium charcoal or platinum charcoal catalytic hydrogenolysis at normal temperatures.
(d2), ester or acid are reduced into the primary alconol reaction
Chemical formula (VIII) (B=SO 2R 5, R 5Be alkyl or substituted hydrocarbon radical) ester or its hydrolysate acid, can be reduced into the alcohol of chemical formula (VII) by currently known methods.For example the ester of chemical formula (VIII) is used copper-chromium (Copper chromile) catalytic hydrogenation or is used Lithium Aluminium Hydride, and lithium borohydride is reduced into primary alconol, and the hydrolysate acid of chemical formula (VIII) becomes primary alconol with borane reduction.In the reduction reaction process, the chiral centre of compound (VIII) keeps configuration.
(d3) deaminizating protecting group reaction
In (VI) formula and (VII) formula compound, Z is that the compound of hydrogen atom can be-SO by Z 2R 5The base or-COR 5Base (R wherein 5Be alkyl or substituted hydrocarbon radical) compound deaminizating protecting group obtain.
The invention provides the racemization of following chemical formula I or optical activity N-isopropyl benzene sulfonamide derivatives and preparation method thereof,
Figure 9410743200141
X wherein 1, X 2, X 3, Y, Z, R 1, R 2Has implication as mentioned above with A.If A is-CH 2OR base (wherein R is the protecting group of hydroxyl) then is the compound of chemical formula VI, if A is-CH 2The OH base then is the compound of chemical formula (VII); If A is-COOR 3Base (R 3Be the alkyl or the suitable protecting group of carboxyl of 1 to 6 carbon), then be the compound of chemical formula (VIII).
The compound of the chemical formula (VII) that makes by the several reactions steps of above-mentioned reaction synoptic diagram (A), the two step reactions steps of passing through following reaction synoptic diagram (B) again are converted into the racemization of chemical formula (X V) or have optical activity 3-alkyl-3,4-dihydro-2H-[1,4] benzo-oxazine derivatives:
Reaction synoptic diagram (B)
Figure 9410743200142
X wherein 1, X 2, X 3, Y, R 1And R 2Have implication as mentioned above, Z is a hydrogen atom ,-CH=C (COOR 4) 2Base, (R 4Alkyl for 1-6 carbon) ,-SO 2R 5The base or-COR 5(R 5Be alkyl or replace hydro carbons), p-toluenesulfonyl for example, benzenesulfonyl, methylsulfonyl, the phenacyl alkylsulfonyl, trifluoromethyl sulfonyl etc., perhaps as benzoyl, carbobenzoxy, formyl radical, ethanoyl, trifluoroacetyl group etc.Preferably p-toluenesulfonyl or benzoyl.
Reactions steps e), ring-closure reaction
Compound cyclization in the presence of alkali of chemical formula (VII) becomes the compound of chemical formula (V).Suitable alkali comprises metal hydride such as hydrolith, sodium hydride, potassium hydride KH etc.; Comprise metal alkyl oxide such as potassium tert.-butoxide etc.; Comprise alkaline carbonate such as yellow soda ash, salt of wormwood etc.; Also comprise fluorochemical such as Potassium monofluoride, tetrabutylammonium.Ring-closure reaction is such as dimethyl sulfoxide (DMSO), N, and dinethylformamide, 1, the 2-glycol dimethyl ether, two (2-methoxyl group) ether, the tetrahydrochysene furan is fed, and in the aprotic solvent of dioxane and chlorobenzene and so on, and carries out in the boiling temperature scope in room temperature.
Through ring-closure reaction, the asymmetric chiral carbon configuration in chemical formula (VII) compound does not change.So, can make the optically active compound of the chemical formula (V) of same chiral configuration from the compound of optical activity chemical formula (VII).
Reactions steps f) deaminizating protecting group reaction
(Z is-SO the amino protecting group Z of chemical formula (V) compound 2R 3The base or-COR 5Base) under corresponding known deprotection method condition, leaves away.For example under acid hydrolysis or reductive cleavage condition, amino p-toluenesulfonyl can be sloughed and dissociate amino.It should be noted that in taking off alkylsulfonyl protecting group reaction process, the compound chirality configuration of chemical formula (V) is constant.Thereby can make the compound of the chemical formula (X V) of same chiral configuration from the compound of optical activity chemical formula (V).
Therefore, the invention provides the racemization of chemical formula (X V) or chemical formula (V) or have preparation method's (see reaction synoptic diagram (A) and (B)) of the novelty of optically active compound, comprising Levofloxacin intermediate (S)-(-)-7,8-two fluoro-3,4-dihydro-3-methyl-2H-[1,4] benzoxazine (X V, X 1=X 2=F, X 3=H, R 1=Me, R 2=H) preparation method.
With compound of the present invention (I) as intermediate preparation (S)-(-)-7,8-two fluoro-3,4-dihydro-3-methyl-2H-[1,4] benzoxazines are compared with background technology, have overcome the shortcoming in the background technology, and nearly all intermediate at room temperature is a solid in the inventive method, easily separated and purifying, no column chromatography operation, easy to use, help scale operation.
Following examples will the invention will be further described, rather than to its restriction.
Embodiment 1:
2,3,4-trifluoromethyl aniline hydrochloride [(XII) HCl, X 1=X 2=Y=F, X 3=H] preparation
2,3,4-trifluoronitrobenzene (20g), the mixture of ethanol (200ml) and 5% palladium charcoal (8.3g) are in room temperature normal pressure catalytic hydrogenation, and after reaction absorbed calculated amount hydrogen, elimination palladium charcoal added concentrated hydrochloric acid (10.3ml), concentrates, and reclaims ethanol.Resistates petroleum ether, suction filtration obtain light green title compound (20.57g).Fusing point is 101.5-110 (decomposition).This product does not need further refining next step reaction that is used for.
Embodiment 2:
2,3,4-three fluoro-N-p-toluenesulfonyl aniline (III, X 1=X 2=Y=F, X 3=H, C=Ts)
In ice bath and under agitation condition, (4.15g) joins 2,3 in batches with Tosyl chloride, and 4-trifluoromethyl aniline hydrochloride (4g) is in the solution of pyridine (7.1ml) and methylene dichloride (40ml).This mixture stirring reaction 20 hours.Add dilute hydrochloric acid solution.Organic layer extracts with dilute sodium hydroxide.The extraction liquid washed with dichloromethane neutralizes with dilute hydrochloric acid again.Obtain white solid, suction filtration, washing obtains title compound (5.86g) after the drying.Molten point is 120.5-121.3 ℃.
1H nucleus magnetic resonance (CCl 4) δ: 2.40 (3H, s), 6.65-7.10 (1H, m), 7.10-7.50 (1H, m), 7.25 (2H, d, J-9Hz), 7.7 (2H, d, J-9Hz).
Embodiment 3:
N-(1-ethoxycarbonyl-ethyl)-N-(2,3, the 4-trifluorophenyl)-para toluene sulfonamide (VIII, X 1=X 2=Y=F, X 3=H, B=Ts, R 1+ R 2-Me+H, R 3=El)
In 2; 3; 4-three fluoro-N-p-toluenesulfonyl aniline (add toluene (10ml) in 100mg, 2N sodium hydroxide (0.175ml) and water (0.6ml) mixing solutions; tetra-n-butyl ammonium bromide (30mg) and 2-(tolysulfonyl oxygen base) ethyl propionate (90mg); reaction mixture stirring and refluxing 18.5 hours under nitrogen protection; after the cooling; filter insoluble substance; filtrate is used dilute hydrochloric acid respectively; dilute sodium hydroxide liquid and water washing; the organic layer anhydrous magnesium sulfate drying concentrates and obtains title compound (107mg).
1H nucleus magnetic resonance (CCl 4) δ: 1.25 (3H, 1, J-7Hz), 1.26 (3H, d, J-7Hz), 2.46 (3H, s), 4.10 (2H, q, J-7Hz), 4.86 (1H, q, J-7Hz) 6.65-7.10 (1H, m), 7.10-7.50 (1H, m), 7,25 (2H, d, J-8.5Hz), 7.62 (2H, d, J=8.5Hz).
Embodiment 4:
(R)-(-)-N-(1-ethoxycarbonyl-ethyl)-N-(2,3, the 4-trifluorophenyl)-para toluene sulfonamide (VIII, X 1=X 2=Y=F, X 3=H, B=Ts, R 1=H, R 2=Me, R 3=Et)
Press embodiment 3 working method, 2,3,4-three fluoro-N-para toluene sulfonamides (10.0g) with (S)-(-)-2-(tolysulfonyl oxygen base) ethyl propionate (9.04g) ([a] B23-28.16, C=2.2, CHCl 3) generation N-alkylation reaction generation title compound (12.27g).[α] D 22.5-1.345，(C=4.4，CHCl 3)。
Embodiment 5:
(S)-(+)-N-(1-ethoxycarbonyl)-N-(2,3, the 4-trifluorophenyl)-para toluene sulfonamide (VIII, X 1=X 2=Y=F, X 3=H, B=Ts, R 1=Me, R 2=H, R 3=Et)
Press embodiment 3 working method, 2,3,4-three fluoro-N-para toluene sulfonamides (15.0g) with (R)-(+)-2-(tolysulfonyl oxygen base) ethyl propionate (13.56g) ([α] D 2035.35, C=2, CHCl 3) the N-alkylation reaction takes place obtain title compound (16.7g).
Embodiment 6:
N-(1-methyl-2-benzyloxy ethyl)-N-(2,3, the 4-trifluorophenyl)-para toluene sulfonamide (VI, X 1=X 2=Y=F, X 3=H, Z=Ts, R 1+ R 2=Me+H, R=PhCH 2)
By similar embodiment 3 working method, 2,3, the N-alkylation reaction (106mg) takes place with 1-benzyloxy-2-tolysulfonyl oxygen base propane (fusing point 44.5-46 ℃) and obtains title compound (115mg) in 4-three fluoro-N-para toluene sulfonamides (100mg).Fusing point is 94,5-96.5 ℃.
Embodiment 7:
N-(1-methyl-2-hydroxyethyl)-N-(2,3, the 4-trifluorophenyl)-para toluene sulfonamide (VIII, X 1=X 2=Y=F, X 3=H, Z=Ts, R 1+ R 2=Me+H)
Under agitation condition, absolute ether (2ml) solution of the product (460mg) that dropping embodiment 3 obtains in the muddy liquid of past Lithium Aluminium Hydride (76mg) and absolute ether (2ml).Stir under this mixture room temperature after 2 hours, add Na 2SO 410H 2O filters, filtrate concentrate light yellow crystal.Use 95% ethanol-sherwood oil (30-60 ℃) recrystallization again, thereby obtain the title compound (313mg) of white crystal.Fusing point is 124-126 ℃.
1H nucleus magnetic resonance (CDCl 3) δ: 0.97 (d, 3H, J=7Hz), 2.00 (s, 1H), 2.43 (S, 3H), 3.00-3.65 (m, 2H), 4.35 (m, 1H), 6.70-7.32 (m, 2H), 7.30 (d, 2H, J=8.5Hz), 7.72 (d, 2H, J=8.5Hz)
Embodiment 8:
N-(1-methyl-2-hydroxyethyl)-N-(2,3, the 4-trifluorophenyl)-para toluene sulfonamide (VII, X 1=X 2=Y=F, X 3=H, Z=Ts, R 1+ R 2=Me+H)
The product (50mg) that embodiment 6 obtains, the mixture of ethyl acetate (10ml) and 5% palladium charcoal (30mg), the room temperature normal pressure leads to hydrogen.After hydrogenolysis was intact, elimination palladium charcoal reclaimed solvent and gets white solid, and with sherwood oil (30-60 ℃) washing, suction filtration obtains title compound (35mg).Fusing point is 124.5-126.5 ℃.
Product Rf value-sample of the Rf value of its TLC and embodiment 7.
Embodiment 9:
(R)-(-)-N-(1-methyl-2-hydroxyethyl)-N-(2,3, the 4-trifluorophenyl)-para toluene sulfonamide (VIII, X 1=X 2=Y=F, X 3=H, Z=Ts, R 1=H, R 2=Me)
Press embodiment 7 working method, the product (5.00g) that makes with Lithium Aluminium Hydride (678mg) reduction embodiment 4, thus obtain title compound (2.82g).Fusing point is 83-85.5 ℃.[α] D 23-47.7(C=2，CHCl 3)。
Embodiment 10:
(S)-(+)-N-(1-methyl-2-hydroxyethyl)-N-(2,3, the 4-trifluorophenyl)-para toluene sulfonamide (VIII, X 1=X 2=Y=F, X 3=H, Z=Ts, R 1=Me, R 2=H).
Press embodiment 7 working method, the product (11g) that makes with Lithium Aluminium Hydride (1.4g) reduction embodiment 5, thus obtain title compound (6.57g).Fusing point is 81.5-83.2 ℃, [α] D 19.551.43 (C=2, CHCL 3).
Embodiment 11:
7,8-two fluoro-3,4-dihydro-3-methyl-4-p-toluenesulfonyl-2H-[1,4] benzoxazine (V, X 1=X 2=F, X 3=H, Z=Ts, R 1+ R 2=Me+H).
7,8-two fluoro-3,4-dihydro-3-methyl-2H-[1,4] benzoxazine (0.25g) is (by 2-acetone oxygen base-3, the 4-difluoro nitrobenzene is pressed EP47005 method preparation), the mixture stirring of methylene dichloride (5ml) and pyridine (0.81g) 15 minutes, add Tosyl chloride (0.26g) again.Reaction solution under agitation refluxed 20 hours.Cooling is with dilute hydrochloric acid and washed several times with water.Tell organic layer, with concentrating behind the anhydrous magnesium sulfate drying.Residue (0.305g) is separated out crystallization, gets title compound (0.190g) with tetracol phenixin-sherwood oil recrystallization.Fusing point is 121-122.5 ℃.Mass spectrum: 339 (M +).
1H nucleus magnetic resonance (CDCl 3) δ: 1.23 (d, 3H, J=7H 2), 2.41 (s, 3H), 3.2 (dd, 1H, J1=3Hz, J2=11Hz), 3.96 (d, 1H, J=11Hz), 4.5 (m, 1H), 6.4-7.1 (m, 1H), 7.25 (d, 2H, J=8.5Hz), 7.52 (d, 2H, J=8.5Hz), 7.55-7.93 (m, 1H).
Embodiment 12:
7,8-two fluoro-3,4-dihydro-3-methyl-4-p-toluenesulfonyl-2H-[1,4] benzoxazine (V, X 1=X 2=F, X 3=H, Z=Ts, R 1+ R 2=Me+H).
N-under 120 ℃ temperature (1-methyl-2-hydroxyethyl)-N-(2,3, the 4-trifluorophenyl)-para toluene sulfonamide (75mg) (product that obtains by embodiment 7), N, the mixture stirring reaction of dinethylformamide (7.5ml) and salt of wormwood (58mg) 1 hour 20 minutes, the elimination insoluble substance is concentrated filtrate then.The residue that is generated ethanol-sherwood oil (30-60 ℃) crystallization, thus white title compound (62mg) obtained.Fusing point is 122-123.5 ℃.Mass spectrum: 339 (M +)
1The product that H-NMR collection of illustrative plates and embodiment 11 obtain 1The H-NMR collection of illustrative plates is the same.
Embodiment 13:
(R)-(+)-7,8-two fluoro-3,4-dihydro-3-methyl-4-p-toluenesulfonyl-2H-[1,4] benzoxazine (V, X 1=X 2=F, X 3=H, Z=Ts, R 1=H, R 2=Me
Press embodiment 12 working method, ring-closure reaction takes place in the product that embodiment 9 makes (0.74g), thereby obtains title compound (0.55g).Fusing point is 128.5-131 ℃.Mass spectrum: 339 (M +).
Embodiment 14:
(S)-(-)-7,8-two fluoro-3,4-dihydro-3-methyl-4-p-toluenesulfonyl-2H-[1,4] benzoxazine (V, X 1=X 2=F, X 3=H, Z=Ts, R 1=Me, R 2=H)
Press embodiment 12 working method, ring-closure reaction takes place in the product that embodiment 10 makes (1g), thereby obtains title compound (0.73g).Fusing point is 128-131 ℃, [α] D 27-114.96 (C=1, CHCl 3),
Embodiment 15:
7,8-two fluoro-3,4-dihydro-3-methyl-2H-[1,4] benzoxazine (XV, X 1=X 2=F, X 3=H, R 1+ R 2=Me+H)
Under logical nitrogen and agitation condition, drip the solution that naphthalene (840mg) and glycol dimethyl ether (3ml) form in the mixture of past granular metal sodium (152mg) and glycol dimethyl ether (3ml).Reaction solution becomes dark green and black.Continue to stir 1 hour 40 minutes, drip the solution of product (30mg) in glycol dimethyl ether (3ml) that embodiment 12 makes then.Mixture stirred after 2 hours, added entry (0.12ml) and concentrated hydrochloric acid (0.55ml) successively, concentrated again.Resulting residue (after 5 * 2ml) washings, extracts with ethanol (7ml) through ether.The elimination insolubles.Filtrate concentrates.The enriched material water dissolution, the elimination insolubles is transferred the filtrate alkalize with dilute sodium hydroxide then again.And extract with benzene.Organic layer washes with water, uses anhydrous magnesium sulfate drying again.Concentrate then.Thereby obtain title compound (10mg).
The Rf of its TLC and 1The H nuclear magnetic resonance data with press the EP47005 method by 2-acetone oxygen base-3, the Rf of the title compound that the 4-difluoro nitrobenzene makes reaches 1The H nuclear magnetic resonance data is the same.
1H nucleus magnetic resonance (CCl 4) δ, 1.20 (d, 3H, J-6Hz), 3.2-3.67 (m, 2H) 3.8 (t, 1H, J 1=8Hz), 4.23 (dd, 1H, J 1=2Hz, J 2=10Hz), 6.2 (m, 1H).6.5(m，1H)。
Embodiment 16:
(R)-(+)-and 7.8-two fluoro-3,4-dihydro-3-methyl-2H-[1,4] benzoxazine (X V, X 1=X 2=F, X 3=H, R 1=H, R 2=Me)
Press embodiment 15 working method, the product that embodiment 13 makes (0.400g) deaminize protecting group, the amine that dissociates, thus obtain title compound (0.199g).[α] D 17+ 8.199 (C-1.66, CHCL 3), mass spectrum, 185 (M +).
Embodiment 17:
(S)-(-)-7,8-two fluoro-3,4-dihydro-3-methyl-2H-[1,4] benzoxazine (X V, X 1=X 2=F, X 3=H, R 1=Me, R 2=H)
Press embodiment 15 working method, the product that embodiment 14 makes (0.400g) deaminize protecting group, the amine that dissociates, thus obtain title compound (0.110g).[α] D 27-7.85(C-2.2，CHCl 3)。
Repeat top-operation, the product (0.235g) that makes from embodiment 15 prepares title compound (0.100g).
1H nucleus magnetic resonance (CCl 4): δ 1.183 (d, 3H, J=6Hz), 3.183-3.6 (m, 2H), 3.73 (t, 1H, J 1=10Hz, J 2=8Hz), 4.2 (dd, 1H, J 1=10Hz, J 2=2.5Hz), 6.2 (m, 1H), 6.5 (m, 1H).

Claims (9)

1. following formula racemization or have optically active compound, its chemical formula is:
Figure 9410743200021
Wherein z is a p-toluenesulfonyl, and A is CH 2It is CH that OR or COOR work as A 2During OR, R is hydrogen or hydroxyl protecting group, and when A was COOR, R was the protecting group of hydrogen or carboxyl.
2. by the compound of claim 1, wherein A is ethoxycarbonyl, 1-methyl-2-hydroxyl, 1-methyl-2-benzyloxy.
3. by the compound of claim 1, chemical name is (S)-(+)-N-(1-methyl-2-hydroxyethyl)-N-(2,3, the 4-trifluorophenyl)-right-toluol sulfonamide.
4. by the compound of claim 1, chemical name is (R)-(-)-N-(1-methyl-2-hydroxyethyl)-N-(2,3, the 4-trifluorophenyl)-right-toluol sulfonamide.
5. by the compound of claim 1, chemical name is (±)-N-(1-methyl-2-hydroxyethyl)-N-(2,3, the 4-trifluorophenyl)-right-toluol sulfonamide.
6. by the compound of claim 1, chemical name is (±)-N-(1-methyl-2-benzyloxy ethyl)-N-(2,3, the 4-trifluorophenyl)-right-toluol sulfonamide.
7. by the compound of claim 1, chemical name is (S)-N-(1-ethoxycarbonyl-ethyl)-N-(2,3, the 4-trifluorophenyl)-right-toluol sulfonamide.
8. by the compound of claim 1, chemical name is (R)-N-(1-ethoxycarbonyl-ethyl)-N-(2,3, the 4-trifluorophenyl)-right-toluol sulfonamide.
9. by the compound of claim 1, chemical name is (±)-N-(1-ethoxycarbonyl-ethyl)-N-(2,3, the 4-trifluorophenyl)-right-toluol sulfonamide.
CN94107432A 1994-07-21 1994-07-21 Intermediate of pyrido-benzoxazine derivative and prepn. method Expired - Fee Related CN1066136C (en)

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