CN105431415A

CN105431415A - Novel synthetic processes to 8-chloro-3-benzo[d]azepine via friedel-crafts alkylation of olefin

Info

Publication number: CN105431415A
Application number: CN201480041113.4A
Authority: CN
Inventors: G·斯塔夫伯; J·克吕佐
Original assignee: Lek Pharmaceuticals dd
Current assignee: Lek Pharmaceuticals dd
Priority date: 2013-05-20
Filing date: 2014-05-19
Publication date: 2016-03-23
Also published as: EP2999692A1; WO2014187768A1

Abstract

The present invention is directed to a short, facile, effective and industrially applicable process for obtaining 8-chloro-l-methyl-2,3,4,5-tetrahydro-lH- benzo[d]azepine, or its salt, preferably lorcaserin hydrochloride. The present invention is further directed to a simple and effective ring closing methodology for obtaining 8-chloro-l-methyl-2,3,4,5-tetrahydro-lH- benzo[d]azepine, or its salt, preferably lorcaserin hydrochloride. The present invention is also directed to a novel intermediate which can be suitably used in the process for producing 8-chloro-l-methyl-2, 3,4,5- tetrahydro-lH-benzo[d]azepine, or its salt, preferably lorcaserin hydrochloride and to a process for producing the novel intermediate.

Description

The novel synthesis of the 8-undertaken by the friedel-crafts alkylation of alkene chloro-3-benzo [D] azepine *

The present invention relates to organic synthesis field, particularly relate to benzo [d] azepine serotonin receptor to stimulating activity especially the synthesis of sieve card XiLin (lorcaserin).

background of invention

Obesity strongly affects whole world millions of people and the number of obesity is increasing considerably always.Huge challenge is deposited by pharmacotherapy successful treatment obesity.As the response to this challenge, development concentrates on the 5-HT2C receptor stimulant being used for the treatment of this life-threatening obstacle.Benzo [d] azepine be accredited as the most promising selectivity 5-HT2C receptor stimulant.There is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine of INN name Luo Ka XiLin hydrochloride hydrochloride (formula 1) represents medicine as first of this pharmacology group and is registered.

8-chloro-1-methyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine first prepared with racemic form by Smith & Smith (WO03/0863069).This synthesis is a kind of tediously long typical laboratory operation, and it uses industrial disadvantageous reagent such as trifluoroacetic anhydride, iodine chloride and palladium catalyst.The method is from the 2-easily obtained (4-chloro-phenyl-) ethamine (formula 2); complete by the following method: Heck cyclisation in the molecule carrying out allyl group intermediate (formula 22) under palladium catalyst exists; thus form outer-methylene derivatives (formula 23); it is used Pd/C hydrogenation and deprotection further, obtains sieve card XiLin (schema 1) of racemic formula 9.

Schema 1. generates first synthetic method in racemize sieve card XiLin

After this, being prepared in first in patent application WO05/019179 of sieve card XiLin (formula 1) of optically active is disclosed, it uses the classical optical resolution of the racemic mixture carried out with tartrate.In addition, the document also describes the route of synthesis (schema 2) of use friedel-crafts (Friedel-Crafts) cyclization method that three kinds are improved.

The synthesis in chirality sieve card XiLin that schema 2. is undertaken by chemical optical resolution

Two prior art routes are from 2-(4-chloro-phenyl-) ethylamine (formula 2), but further conversion makes method more effectively simple.Then amino intermediate is used chlorpromazine chloride acidylate; form amide precursor (formula 10); using its cyclisation be finally reduced to racemic sieve card XiLin (formula 9) under existing as the aluminum chloride of Lewis acid reagent, or it is first reduced the compound of an accepted way of doing sth 12 last cyclisation.

It, from 2-(4-chloro-phenyl-) ethanol (formula 7), is first used expensive phosphorus tribromide bromination by the 3rd route.The excessive 1-amino-2-propyl alcohol of the bromide of formula 3 is changed into alcohol precursor (formula 8).After this, described alcohol is replaced by thionyl chloride under the N,N-DIMETHYLACETAMIDE of catalytic amount exists, obtains the solid hydrochloride precursor identical with the formula 12 obtained in second route.

In addition, describe the improvement of the method for schema 2 in WO07/120517, the improvement about the lock out operation of friedel-crafts cyclization product which provides more detailed description, wherein uses SiO ₂-H ₂the quencher of O mixture is reacted.

In the disclosure of patent application WO08/070111 (schema 3), synthesize from the linked reaction of carrying out under various coupling reagent (trifluorophenylboronic acid, phenyl-boron dihydroxide, EDC or toluenesulphonic acids/Propanal dimethyl acetal) exists between 2-(4-chloro-phenyl-) acetic acid (formula 13) and 1-amino-2-propyl alcohol.Then will optionally with a small amount of dihydro various reductive agent (borine in tetrahydrofuran (THF) or methyl-sulfide, sodium borohydride) under iodine the exists reduction of the acid amides (formula 14) of the gained that azole compounds (formula 15) mixes, obtain the alcohol precursor of formula 8, by its as described in foregoing disclosure thing change into sieve card XiLin (formula 1) further.

Schema 3. is by 2-kharophen and dihydro the synthesis that azoles precursor carries out

In addition, publication WO09/111004 describes the other improvement of the method for schema 2, and it uses new bromination process, comprises the PBr by Hbr gas instead costliness ₃(schema 4).This publication further discloses the problematic di of the bromide of 1-amino-2-propyl alcohol and formula 3, its impurity shown in production 16, and this impurity is reduced to the content being less than 10% in the product of required formula 8.

The improvement of the synthetic method that schema 4. is undertaken by Bromo-intermediates

Another publication (WO10/148207) discloses the other improvement of the method for schema 2 and 4, and it uses new chlorination method, and the method thionyl chloride replaces dangerous HBr gas and expensive PBr ₃.Also describe the reaction (schema 5) of compound 17 and 1-amino-2-propyl alcohol.

The improvement of the synthetic method that schema 5. is undertaken by chloro intermediate

The known route shown in schema 2-5 above requires the various halogenated intermediates of preparation, and it causes a large amount of synthesis steps.Although there is above-mentioned various improvement, they still need corrosive reagents, such as phosphorus tribromide, gaseous hydrogen bromide or thionyl chloride.Halogenated intermediates is determining presence of genotoxic compound, and discharges corrosive hydrogen halides in friedel-crafts cyclization process.

To exploitation is new, simple and the industrial acceptable method preparing sieve card XiLin or allied compound exists strong interest.Special focus is also last synthesis step, and wherein closed last intermediate represents huge obstacle and challenge with the effective ways generating sieve card XiLin or allied compound.

summary of the invention

The object of this invention is to provide a kind of short, easily, effective and industrial applicable acquisition 8-chloro-1-methyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine the method of (formula 9) or its salt, preferably sieve card XiLin hydrochloride (formula 1).Another object of the present invention is to provide simply a kind of and effectively obtains 8-chloro-1-methyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine the ring method of closing of (formula 9) or its salt, preferably sieve card XiLin hydrochloride (formula 1).Another object of the present invention is to provide one and is suitable for use in production 8-chloro-1-methyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine new intermediate in the method for (formula 9) or its salt, preferably sieve card XiLin hydrochloride (formula 1) and produce the method for this new intermediate.

Entry below summarizes alone or in combination together to the contributive aspect of described object of the present invention and preferred feature or embodiment.

1. prepare the chloro-1-methyl-2 of 8-of the formula 9 of (essentiallyenantiopure) form of racemic object form, substantially enantiomer-pure or (enantiopure) form of enantiomer-pure, 3,4,5-tetrahydrochysene-1H-benzo [d] azepine or the method for its salt:

* in its Chinese style represents asymmetric C atom, and described method is passed through

(A) compound of formula 4 is made:

Or (when the there is not solvent) reaction under friedel-crafts reagent (FriedelCraftsreagent) exists under pure condition of its salt is carried out.

2. the method according to entry 1, the compound of its Chinese style 4 is solid salt forms, is preferably selected from hydrobromate or hydrochloride, and wherein said compound is most preferably the hydrochloride of formula 5:

3. the method according to entry 1 or 2, wherein said friedel-crafts reagent is Lewis acid, be preferably selected from transition metal and aluminum compound, more preferably zinc or aluminium salt, preferably salt hydrochlorate is selected from, wherein most preferred Lewis acid is aluminum chloride, and wherein said friedel-crafts reagent, preferably described Lewis acid preferably with excessive molar weight, preferably with the molar excess of 1.1 to 10 times, more preferably used with the molar excess of 1.25 to 2 times.

4. according to the method in entry 1 to 3 described in any one, wherein reactions steps (A) is carry out at the temperature of liquid at mixture, preferably higher than 60 DEG C, more preferably higher than the temperature of 90 DEG C under carry out, most preferably carry out at the temperature of 110-130 DEG C.

5. according to the method in entry 1 to 4 described in any one, wherein reactions steps (A) proceeds to the further consumption that formula 4 compound or its salt can not be detected, preferably carries out at least 2 hours, preferably carries out 2-24 hour, more preferably carry out 4-10 hour, most preferably carry out 6 hours.

6., according to the method in entry 1 to 5 described in any one, wherein said method comprises following post-processing step:

B (), by hot melt is added to quencher reaction mixture in the aqueous solution of water or salt or salt mixture, described reaction mixture is by making (when the there is not solvent) reaction under friedel-crafts reagent exists under pure condition of the compound or its salt of formula 4 obtain; And/or

(c) by product from aqueous extraction to the not miscible solvent of water; And/or

D () isolates the compound or its salt of formula 9;

And wherein said method preferably includes any one in step (b) to (d).

7. the method according to entry 6, wherein in step (b), reaction mixture is cooled to the temperature that it remains liquid, preferably be cooled to 80-100 DEG C, more preferably 85-95 DEG C is cooled to, most preferably be cooled to 90 DEG C, and the quencher of use medium, wherein quench mixture is preferably the aqueous solution, the preferably sodium chloride aqueous solution of inorganic salt, and its concentration is that at least 5% (w/w), preferably 10% (w/w) are to saturated (salt solution).

8. the method according to entry 6 or 7, wherein in and by the reaction mixture of quencher after according to step (c) solvent extraction product not miscible with water.

9. the method according to entry 6 or 7, wherein in step (b), use salt solution quencher reaction mixture, and wherein neutralize by the reaction mixture of quencher in step (c), but with the not miscible solvent of water, preferably dichloromethane extraction product, it is the hydrochloride form of formula 6:

And the hydrochloride wherein by evaporating and described in the not miscible separated from solvent of water in step (d), and wherein optionally by resistates solvent again suspendible or recrystallization, thus obtain product that is crystalline, purifying.

10. according to the method in entry 6 to 9 described in any one, wherein said is selected from ether, ester, haloalkane, aromatics or aliphatic hydrocrbon or its mixture with the not miscible solvent of water, be preferably selected from haloalkane and ester, and if use salt solution, can be miscible with the not miscible solvent of salt solution such as C with pure water but be also selected from ₄-C ₅alcohol, tetrahydrofuran (THF) and acetonitrile, and wherein as being especially preferred with the not miscible methylene chloride of water.

11. according to the method in entry 6 to 8 and 10 described in any one, in step (d), wherein gone out the compound of the formula 9 of alkali (unhindered amina) form by evaporation and the not miscible separated from solvent of water.

12. according to the method in entry 6 to 8,10 and 11 described in any one, wherein pass through in solvent such as acetone or ether with the hydrochloride of the compound of HCl process formula 9 by a converting compounds accepted way of doing sth 6 for formula 9, and wherein optionally by resistates solvent again suspendible or recrystallization, thus obtain product that is crystalline, purifying.

13. according to the method in entry 1 to 12 described in any one, and wherein said method generates racemic mixture or its salt of formula 9 compound, and it is preferably the compound of formula 6.

14. according to the method in entry 1 to 13 described in any one, and wherein said method is further comprising the steps of:

(e) converting compounds of formula 6 or 9 is become enantiomer-pure substantially or sieve card XiLin hydrochloride of formula 1 of enantiomer-pure:

This conversion realizes by the following method: carry out chiral separation by the selective crystallization carrying out diastereomeric salt with resolution reagent, preferably tartrate, then carry out anionresin.

15. according to the method in entry 1 to 14 described in any one, and described method is further comprising the steps of:

(A ') make compd A and B reaction,

Thus the compound or its salt of formula 4 is obtained in nucleophilic substitution reaction or in reductive amination reaction; If wherein-X is-NH ₂, then-Y is leavings group, and described leavings group is preferably selected from halogen or-OSO ₂r, if or-X be carbonyl (=O; I.e. A=(4-chloro-phenyl-) acetaldehyde) or leavings group, described leavings group is preferably selected from halogen or-OSO ₂r, then-Y is-NH ₂;

Wherein said halogen is selected from chlorine, bromine or iodine, and R is selected from the C1-C4 alkyl of unsubstituted or fluoro or phenyl that is unsubstituted or that be substituted; And

Wherein for described nucleophilic substitution reaction, amine compound is preferably molar excess for the compound with leavings group, wherein the molar excess of amine compound is more preferably 1.1 to 10 times, described reaction is optionally carried out under solvent and alkali exist, described solvent is preferably selected from dimethyl sulfoxide (DMSO), acid amides, nitrile, cyclic ether, haloalkane, aromatic hydrocarbon and ester, more preferably tetrahydrofuran (THF) is selected from, described alkali is preferably selected from alkali-metal oxyhydroxide, carbonate and C1-C5 alkoxide, more preferably carbonate is selected from, such as salt of wormwood; And

Wherein for the reaction of described reductive amination, use applicable reductive agent, be preferably selected from H ₂/ Pd/C, sodium borohydride, sodium cyanoborohydride and sodium triacetoxy borohydride.

16. methods according to entry 15, wherein said method comprises following post-processing step:

(b ') optionally, if it is extractible that the compound derived from leavings group is organic phase, the reaction mixture obtained after making compd A and B reaction with alkaline aqueous phase washing, wherein said alkaline aqueous phase is preferably selected from the aqueous solution of alkali bicarbonate, carbonate, phosphoric acid salt or oxyhydroxide, is preferably selected from sodium carbonate or salt of wormwood; And/or

(c ') is by evaporation removing volatile compound; And/or

(d ') adds the aqueous solution, preferably sodium chloride solution, more preferably 10% (w/w) sodium chloride solution of one or more inorganic salt to the sodium chloride solution (salt solution) of saturation concentration in resistates, and preferably add hydrochloric acid to obtain the compound of formula 5, it is preferably used with the aqueous solution form of 0.5-10 volumetric molar concentration; And/or

(e ') with the not miscible solvent of water or solvent extraction product not miscible with salt solution, described is preferably selected from haloalkane and ester with the not miscible solvent of water, described with the not miscible solvent of salt solution such as C4-C5 alcohol, tetrahydrofuran (THF), acetonitrile, methyl ethyl ketone or methyl acetate, wherein methylene dichloride is most preferred Extraction solvent; And/or

(f ') is except desolventizing; And/or

(g ') suspendible resistates, is preferably suspended in resistates in acetone or isopropyl acetate; And/or

(h ') separate solid product, wherein said separated product is undertaken by any solid-liquid isolation technique, and described solid-liquid isolation technique is preferably selected from filtration or centrifugal.

17. methods according to entry 16, it comprises any one in step (c ') to (h '), optionally comprise (b ').

18. according to the method in entry 15 to 17 described in any one, and wherein said leavings group is bromine.

19. according to the method in entry 15 to 17 described in any one, and wherein said leavings group is-OSO ₂r, it can be prepared optionally by following methods: make corresponding alcohol and SULPHURYL CHLORIDE RSO ₂cl or acid anhydride (RSO ₂) ₂o reacts in the presence of a base, wherein R is with defined identical above, and the sulfonic acid allyl ester of wherein preferably not separating obtained sulfonic acid 4-chlorobenzene ethyl ester (formula A ') or gained (formula B '), but by its in single tank (onepot) operation or original position be used in the step of the compound or its salt of preparation formula 4, the compound of preferred formula 5.

20. methods according to entry 19, the sulfonic acid 4-chlorobenzene ethyl ester of its Chinese style A ' is reacted by the styroyl alcohol of formula 7 and corresponding SULPHURYL CHLORIDE and produce under inorganic or organic bases exist, in a solvent, and wherein R is preferably methyl or 4-aminomethyl phenyl:

Described inorganic or organic bases is preferably selected from tertiary amine such as triethylamine, diisopropyl ethyl amine and/or 4 _-dimethyl aminopyridine, described solvent is preferably selected from hydrochloric ether, aromatic hydrocarbon or pyridine, if wherein solvent is pyridine, does not then need other organic bases.

21. methods according to entry 19, the sulfonic acid allyl ester of its Chinese style B ' is reacted by allyl alcohol and corresponding SULPHURYL CHLORIDE and produce under inorganic or organic bases exist, in a solvent, and wherein R is preferably methyl or 4-aminomethyl phenyl:

22. according to the method in entry 15 to 18 described in any one, wherein 4-chlorobenzene ethyl bromine reacts when there is not solvent and other alkali with the allyl amine of at least 5 times of molar excess, obtain the compound of formula 5, preferably obtain the compound of formula 5 at least step (c ') use HCl in step (d ') after to the process of (h ').

23. according to the method in entry 15 to 18 described in any one, wherein excessive on a small quantity 4-chlorobenzene ethyl amine and allyl bromide 98 react in the tetrahydrofuran (THF) as solvent and the salt of wormwood as alkali, obtain the compound of formula 5, preferably in step (d '), use HCl to obtain the compound of formula 5 to the process of (h ') according at least step (d ').

24. according to the method in entry 15 to 17 described in any one, and wherein allyl amine and (4-chloro-phenyl-) acetaldehyde react through reducing in reductive amination reacts, and preferably use H ₂/ Pd/C.

25. according to the method in entry 15 to 21 and 24 described in any one, the compound of its Chinese style 4 prepares according to the operation of step (A '), comprise at least step (b ') and, to (f '), in step (d '), do not use HCl.

26. prepare enantiomer-pure substantially or the method for sieve card XiLin hydrochloride of formula 1 of enantiomer-pure:

It carries out according to the following steps:

(A ') make compd A and B reaction,

Wherein for the reaction of described reductive amination, use applicable reductive agent, be preferably selected from H ₂/ Pd/C, sodium borohydride, sodium cyanoborohydride and sodium triacetoxy borohydride;

(b ') optionally use alkaline aqueous phase washing reaction mixture;

(c ') by evaporation removing volatile compound;

(d ') adds the aqueous solution and the hydrochloric acid of one or more inorganic salt in resistates, the preferred sodium chloride solution of the aqueous solution of described inorganic salt, more preferably 10% (w/w) sodium chloride solution is to the sodium chloride solution (salt solution) of saturation concentration, and described hydrochloric acid is preferably used with the aqueous solution form of 0.5-10 volumetric molar concentration;

(e ') is with the not miscible solvent of water, preferably use dichloromethane extraction product;

(f ') except desolventizing;

(g ') suspendible resistates, preferably resistates is suspended in acetone or isopropyl acetate;

(h ') isolates the solid product of formula 5;

(A) (when the there is not solvent) reaction under friedel-crafts Lewis acid reagent exists under pure condition of the compound of formula 5 is made, described friedel-crafts Lewis acid reagent is preferably aluminium salt or zinc salt, is most preferably aluminum chloride;

B (), by reaction mixture being joined quencher reaction mixture in sodium chloride aqueous solution, the concentration of described sodium chloride aqueous solution is that 10% (w/w) is to saturation concentration (salt solution);

C () extracts product from aqueous phase, preferably extract in methylene dichloride;

D () isolates the compound of formula 6;

(e) converting compounds of formula 6 is become enantiomer-pure substantially or sieve card XiLin hydrochloride of formula 1 of enantiomer-pure, this conversion realizes by the following method: carry out chiral separation by the selective crystallization carrying out diastereomeric salt with resolution reagent, preferably tartrate, then carry out anionresin.

27. prepare enantiomer-pure substantially or the method for sieve card XiLin hydrochloride of formula 1 of enantiomer-pure:

It carries out according to the following steps:

(A ') make compd A and B reaction,

(b ') optionally use alkaline aqueous phase washing reaction mixture;

(c ') by evaporation removing volatile compound;

(f ') except desolventizing is to isolate thick formula 5 compound;

(A) (when the there is not solvent) reaction under friedel-crafts Lewis acid reagent exists under pure condition of thick formula 5 compound is made, described friedel-crafts Lewis acid reagent is preferably aluminium salt or zinc salt, is most preferably aluminum chloride;

D () isolates the compound of formula 6;

(e) converting compounds of formula 6 is become enantiomer-pure substantially or sieve card XiLin hydrochloride of formula 1 of enantiomer-pure, this conversion realizes by the following method: carry out chiral separation by the selective crystallization carrying out diastereomeric salt with tartrate, then carry out anionresin.

28. in the synthesis of single tank, prepare enantiomer-pure substantially or the method for sieve card XiLin hydrochloride of formula 1 of enantiomer-pure:

It carries out according to the following steps:

(A ') make compd A and B reaction,

(c ') by evaporation removing volatile compound, thus obtain the resistates comprising thick formula 4 compound or its salt;

(A) (when the there is not solvent) reaction under friedel-crafts Lewis acid reagent exists under pure condition of described resistates is made, described friedel-crafts Lewis acid reagent is preferably aluminium salt or zinc salt, is most preferably aluminum chloride;

F () isolates the compound of formula 6;

(g) converting compounds of formula 6 is become enantiomer-pure substantially or sieve card XiLin hydrochloride of formula 1 of enantiomer-pure, this conversion realizes by the following method: carry out chiral separation by the selective crystallization carrying out diastereomeric salt with resolution reagent, preferably tartrate, then carry out anionresin.

29. according to the method in entry 26 to 28 described in any one, and wherein said compd B is allyl amine, and wherein said compd A is 4-chlorobenzene ethyl bromine.

30. according to the method in entry 26 to 28 described in any one, and wherein said compd B is allyl bromide 98, and described compd A is 4-chlorobenzene ethyl amine.

The hydrochloride of N-allyl group-N-(4-chlorobenzene ethyl) amine of 31. formulas 5:

The hydrochloride of N-allyl group-N-(4-chlorobenzene ethyl) amine of N-allyl group-N-(4-chlorobenzene ethyl) amine of 32. formulas 4 or its salt, preferred formula 5 is for the preparation of the chloro-1-methyl-2 of 8-of racemic formula 9,3,4,5-tetrahydrochysene-1H-benzo [d] azepine or its salt, more preferably for the preparation of enantiomer-pure substantially or sieve card XiLin of enantiomer-pure or its salt, most preferably for the preparation of enantiomer-pure substantially or the purposes of sieve card XiLin hydrochloride of formula 1 of enantiomer-pure.

The method of the hydrochloride of N-allyl group-N-(4-chlorobenzene ethyl) amine of 33. preparation formulas 5:

Described method comprises step below:

(A ') make compd A and B reaction:

Thus the compound of formula 5 is obtained in nucleophilic substitution reaction or in reductive amination reaction;

If wherein-X is-NH ₂, then-Y is leavings group, and described leavings group is preferably selected from halogen or-OSO ₂r, if or-X be carbonyl (=O; I.e. A=(4-chloro-phenyl-) acetaldehyde) or leavings group, described leavings group is preferably selected from halogen or-OSO ₂r, then-Y is-NH ₂;

34. methods according to entry 33, wherein said method comprises post-processing step below:

(b ') optionally, if it is extractible that the compound derived from leavings group is organic phase, the reaction mixture obtained after then making compd A and B reaction with alkaline aqueous phase washing, wherein said alkaline aqueous phase is preferably selected from the aqueous solution of alkali bicarbonate, carbonate, phosphoric acid salt or oxyhydroxide, is preferably selected from sodium carbonate or salt of wormwood; And/or

(c ') is by evaporation removing volatile compound; And/or

(d ') adds the aqueous solution and the hydrochloric acid of one or more inorganic salt in resistates, the preferred sodium chloride solution of the aqueous solution of described inorganic salt, more preferably 10% (w/w) sodium chloride solution is to the sodium chloride solution (salt solution) of saturation concentration, and described hydrochloric acid is preferably used with the aqueous solution form of 0.5-10 volumetric molar concentration; And/or

(f ') is except desolventizing; And/or

35. methods according to entry 34, it comprises any one in step (c ') to (h '), optionally comprise (b ').

36. according to the method in entry 33 to 35 described in any one, and wherein said leavings group is bromine.

37. according to the method in entry 33 to 35 described in any one, and wherein said leavings group is-OSO ₂r, it can be prepared optionally by following methods: make corresponding alcohol and SULPHURYL CHLORIDE RSO ₂cl or acid anhydride (RSO ₂) ₂o reacts in the presence of a base, wherein R is with defined identical above, and the sulfonic acid allyl ester of wherein preferably not separating obtained sulfonic acid 4-chlorobenzene ethyl ester (formula A ') or gained (formula B '), but by its in single tank operation or original position be used in the step of the compound of preparation formula 5.

38. methods according to entry 37, the sulfonic acid 4-chlorobenzene ethyl ester of its Chinese style A ' is reacted by the styroyl alcohol of formula 7 and corresponding SULPHURYL CHLORIDE and produce under inorganic or organic bases exist, in a solvent, and wherein R is preferably methyl or 4-aminomethyl phenyl:

Described inorganic or organic bases is preferably selected from tertiary amine such as triethylamine, diisopropyl ethyl amine and/or 4-dimethylaminopyridine, and described solvent is preferably selected from hydrochloric ether, aromatic hydrocarbon or pyridine, if wherein solvent is pyridine, does not then need other organic bases.

39. methods according to entry 37, the sulfonic acid allyl ester of its Chinese style B ' is reacted by allyl alcohol and corresponding SULPHURYL CHLORIDE and produce under inorganic or organic bases exist, in a solvent, and wherein R is preferably methyl or 4-aminomethyl phenyl:

40. according to the method in entry 33 to 36 described in any one, wherein 4-chlorobenzene ethyl bromine reacts when there is not solvent and other alkali with the allyl amine of at least 5 times of molar excess, obtain the compound of formula 5, preferably obtain the compound of formula 5 at least step (c ') use HCl in step (d ') after to the process of (h ').

41. according to the method in entry 33 to 36 described in any one, wherein excessive on a small quantity 4-chlorobenzene ethyl amine and allyl bromide 98 react in the tetrahydrofuran (THF) as solvent and the salt of wormwood as alkali, obtain the compound of formula 5, preferably obtain the compound of formula 5 at least step (d ') use HCl in step (d ') after to the process of (h ').

42. according to the method in entry 33 to 35 described in any one, and wherein allyl amine and (4-chloro-phenyl-) acetaldehyde react through reducing in reductive amination reacts, and preferably use H ₂/ Pd/C.

detailed Description Of The Invention

Hereinafter, describe in further detail the present invention by referring to the other preferred and other embodiment had superiority and example, these embodiments and example are supplementing entry above, shall not be understood as limiting.

The invention provides industrial applicable, economical and simply prepare 8-chloro-1-methyl-benzo [d] azepine of antagonism thrombotonin or the method for its salt, particularly sieve card XiLin and the new key intermediate prepared for it.Sieve card XiLin is one optionally 5-HT _2Creceptor stimulant, the vitro test of this medicine prove relative to other about for target its to 5-HT _2Cthere is rational selectivity.5-HT in hypothalamus _2Cthe activation of acceptor is considered to activation proopiomelanocortin (proopiomelanocortin, POMC) and produces and therefore promote that body weight lowers by satiety (satiety).For 8-chloro-1-methyl-benzo [d] azepine or its salt, particularly sieve card XiLin, synthetic route as herein described benefits from that reaction is simple, the amount of reaction sequence step reduces, reaction conditions is gentle especially and chemical substance easily obtains.

In order to explain term used in description of the invention, application definition below.Their the usual implication that other terms all used herein are understood according to those of ordinary skill in the art is explained.

Term used herein " not miscible solvent " represents the solvent forming two phases of separating with the medial border that can clearly distinguish with another kind of liquid phase.

Term used herein " single tank " synthesis or two or more reactions of method representation, the product of the reaction wherein is not transferred to start next chemical reaction in second conversion unit, but can carry out some technological operations to remove impurity, solvent or enriched mixture in former container.

Two or more reactions of term used herein " original position " method representation, add new reagent, solvent and/or additive and proceed operation in the reaction mixture before the product of the reaction is wherein retained in.

Term used herein " substantially enantiomer-pure " means the enantiomeric excess of 70%ee or more, preferably 80%ee or more, more preferably 90%ee or more, most preferably 97%ee or more.

Term used herein " salt " refers to the salt form be applicable to arbitrarily of each compound.Preferably, described salt is pharmaceutically acceptable.

According to first aspect, the invention provides 8-chloro-1-methyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine of the formula 9 preparing the form of racemic object form, substantially enantiomer-pure or the form of enantiomer-pure or the method for its salt:

(A) compound of formula 4 is made:

Or its salt (when there is not solvent) under pure condition reacts and carries out under friedel-crafts reagent exists.

By utilizing this reactions steps (A), compared with prior art, the total synthesis step for the preparation of the compound or its salt of formula 6, preferably sieve card XiLin can be reduced.Described synthesis avoids disadvantageous reagent such as trifluoroacetic acid, iodine and the palladium catalyst that Heck cyclisation in the molecule shown in schema 1 is applied.Present invention utilizes the parent material 4 or 5 easily obtained, it can be converted to required product in direct mode easily, thus overcomes the obstacle of last ring closed procedure.

Up to the present, the description about the electrophilic substitution of alkene in Friedel Crafts conditions is considerably less.Such as, the people (Eur.J.Org.Chem.2011,264-270) such as WangJ. reports and uses AlCl ₃1-methoxyl group-2-(the 3-methyl-2-butene base) cyclisation of benzene in biphasic condition carried out.But the mixture of the required product of acquisition contains many by products.The people such as Xie (TetrahedronLett.2010,51,4466-4469) report at FeCl ₃the cyclisation (schema 6) of the alkene under existence in Nitromethane 99Min..There was reported and use allocatalysis agent (Mo (CP) ₆, Bi (OTf) ₃or InCl ₃the another kind of alkene friedel-crafts cyclisation (BeilsteinJ.Org.Chem.2010,6,6) of the styrene derivatives carried out.Also in ion type liquid (MeImEtCl-AlCl3), complete Friedel-Crafts reaction (J.Org.Chem.1986,51,480-483) with alkyl chloride.But, the method for carrying out cyclization of olefines under pure Friedel Crafts conditions was not described in the literature.

The example (people such as Xie) of the FC cyclisation of schema 6. alkene

The present inventor is surprisingly found out that, use pure condition to carry out the friedel-crafts cyclisation of alkene, friedel-crafts cyclisation creates industrial acceptable yield and purity.On the other hand, it is worth mentioning, some describe in solvent such as document those, such as FeCl ₃/ MeNO ₂, FeCl ₃the method of the cyclized by treatment alkene of/AcOH can not produce required product.

By using the novel synthesis of reactions steps (A), present invention achieves additional benefit below:

-under pure condition fusing mutually in the Friedel-Crafts reaction (cyclisation of olefin precursor) that completes more safer than the equivalent method of prior art because do not discharge HCl in reaction process;

-at a higher temperature, Friedel-Crafts reaction usually needs dangerous with poisonous solvent, such as chlorobenzene, 1,2-dichlorobenzene, 1,2-ethylene dichloride, Nitromethane 99Min., oil of mirbane, and pure conditions permit uses high temperature when not using this kind of dangerous solvents, make method more favourable to environment like this;

-do not have solvent to make to react safer with water a large amount of heat release ground quencher at relatively high temperatures, there is no fire risk;

-do not need to remove high boiling solvent;

-discharge less gaseous hydrogen chloride, when especially using zinc chloride;

-lower reaction volume allow to have higher flow gain batch/equipment;

-use reagent and the catalyzer of simple and commercially available acquisition;

-do not need special laboratory equipment and technology.

Common friedel-crafts reagent is all in the method for the invention available, such as, described in WO2005/019179 those.For object of the present invention, preferably use Lewis acid.Described Lewis acid is preferably selected from transition metal and aluminum compound, and it is more preferably selected from zinc or aluminium salt, preferred chloride salt.Most preferred Lewis acid is aluminum chloride.

Friedel-crafts reagent is preferably used with excessive molar weight, preferably 1.1 to 10 times of molar excess, more preferably 1.25 to 2 times of molar excess.

Reaction usually under mixture is the temperature of liquid, preferably higher than 60 DEG C, more preferably carry out at the temperature of 110-130 DEG C higher than at the temperature of 90 DEG C, most preferably.Reaction can proceed to the further consumption that parent material can not be detected.At least 2 hours, preferred 2-24 hour, more preferably 4-10 hour, most preferably 6 hours are carried out in reaction usually.

After reacting completely, the present invention preferably includes the aftertreatment of step (b) to (d) above.

For the aftertreatment of step (b), reaction mixture is preferably cooled to the temperature that it remains liquid.More preferably, its be cooled to 80-100 DEG C, be more preferably cooled to 85-95 DEG C, be most preferably cooled to 90 DEG C.Then, by the quencher of reaction mixture use medium, wherein quench mixture is preferably the aqueous solution of inorganic salt, and preferred concentration is at least 5% (w/w), preferably 10% (w/w) sodium chloride aqueous solution to saturated (salt solution).

Preferably according to step (c) by product from by the aqueous extraction of quencher to the not miscible solvent of water.Therefore, can in a straightforward manner crude product be purified from the by product such as salt of water soluble.Described be preferably selected from the not miscible solvent of water ether, ester, haloalkane, aromatics or the hydrocarbon of aliphatic series or its mixture.More preferably, it is selected from haloalkane and ester.If use salt solution, also can use can miscible but solvent not miscible with salt solution with pure water, such as C ₄-C ₅alcohol, tetrahydrofuran (THF) and acetonitrile.Be particularly preferred as the methylene dichloride with the not miscible solvent of water, it has the hydrochloride that enough polarity extracts required product from aqueous phase even astoundingly.

Finally, preferably product is isolated according to step (d).This separation has normally been come by evaporation and the not miscible solvent of water.Optionally, if the compound of formula 6 is compounds of salt form, preferably formula 9, then resistates solvent suspendible or the recrystallization be again applicable to that can optionally will obtain after evaporation, thus obtain product that is crystalline, purifying.Described solvent compatibly can be selected by those skilled in the art, and can be the solvent described in reference (such as WO2005/019179) of prior art.

In order to obtain the product of formula 9, preferably neutralization is by the aqueous mixture of quencher, then with solvent extraction product not miscible with water, described be preferably selected from the not miscible solvent of water ether, ester, haloalkane, aromatics or the hydrocarbon of aliphatic series or its mixture.Preferred use methylene dichloride.

In order to obtain the product of formula 6, can by the compound of formula 9 to be converted it in solvent such as acetone or ether the hydrochloride of formula 6 with HCl process.As described above, optionally by thus obtained resistates solvent suspendible or the recrystallization be again applicable to, thus product that is crystalline, purifying can be obtained.Or, according to an especially preferred embodiment, can by wherein not neutralizing by the reaction mixture of quencher with salt solution quencher reaction mixture but obtain the compound of formula 6 with the product with the not miscible solvent of water, preferably dichloromethane extraction formula 6.

Utilize reactions steps (A) above, the present invention can produce the compound or its salt of required formula 9, the compound of preferred formula 6, and it is the form of racemoid.

Preferably, the compound of the compound or its salt of formula 9, preferred formula 6 can be converted to enantiomer-pure substantially according to step (e) or sieve card XiLin hydrochloride of formula 1 of enantiomer-pure:

By sieve card XiLin hydrochloride using the tartrate scheme of WO05/019179 racemic formula 6 compound or its salt such as can be changed into the formula 1 of enantiomer-pure.

Preferably, the compound of the formula 4 used in reactions steps (A) is above forms of solid salt, is preferably selected from bromide salt or chloride salt.Most preferably, described compound is the hydrochloride of formula 5.

The compound of formula 5 is the new intermediate compounds be applicable to be used in synthesis of the present invention.It has excellent physical properties in reactive in Friedel-Crafts reaction in fusing mutually, can shorten 3-benzo [d] azepine with the prior art Compound Phase of oiliness alkali form than it synthesis.

According to another aspect, present invention teaches N-allyl group-N-(4-chlorobenzene ethyl) amine of use formula 4 or its salt, preferred formula 5 N-allyl group-N-(4-chlorobenzene ethyl) amine hydrochlorate to the chloro-1-methyl-2 of the 8-preparing racemic formula 9,3,4,5-tetrahydrochysene-1H-benzo [d] azepine or its salt, more preferably prepare enantiomer-pure substantially or sieve card XiLin of enantiomer-pure or its salt, most preferably prepare enantiomer-pure substantially or the suitability of sieve card XiLin hydrochloride of formula 1 of enantiomer-pure.

In second of the present invention, provide the method for step (A ') above, its midbody compound for the production of formula 4 or its salt (it is preferably the compound of formula 5), it compatibly can be used to the parent material described in production first aspect.

In method in second, compd A and B:

Reaction in step (A '), thus in nucleophilic substitution reaction or obtain the compound or its salt of formula 4 in reductive amination reaction, the compound of its preferably formula 5.One of-X and-Y is amino (-NH ₂).

If-X is-NH ₂, then-Y is leavings group, and described leavings group is preferably selected from halogen or-OSO ₂r.Or, if Y is-NH ₂, then-X is carbonyl (=O; I.e. A=(4-chloro-phenyl-) acetaldehyde) or leavings group, described leavings group is preferably selected from halogen or-OSO ₂r.

Described leavings group can be the leavings group that can be used for any routine of carrying out nucleophilic substitution reaction with primary amine.For object of the present invention and owing to easily obtaining and good reactivity, described leavings group is preferably selected from halogen or-OSO ₂r.Halogen is selected from chlorine, bromine or iodine, and R is selected from the C1-C4 alkyl of unsubstituted or fluoro or phenyl that is unsubstituted or that be substituted.Preferably, R is methyl or 4-aminomethyl phenyl, i.e. group-OSO ₂r is methylsulfonic acid ester group (mesylate) or toluenesulphonic acids ester group (tosylate).

For nucleophilic substitution reaction, amine compound is preferably molar excess for the compound with leavings group, and wherein the molar excess of amine compound is more preferably 1.1 to 10 times.

Described reaction is optionally carried out in the presence of solvent and under inorganic or organic bases exist, described solvent is preferably selected from dimethyl sulfoxide (DMSO), acid amides, nitrile, cyclic ether, haloalkane, aromatic hydrocarbon and ester, more preferably tetrahydrofuran (THF) is selected from, described inorganic or organic bases is preferably selected from alkali-metal oxyhydroxide, carbonate and C1-C5 alkoxide, more preferably carbonate is selected from, such as salt of wormwood, or be preferably selected from tertiary amine, such as triethylamine, diisopropyl ethyl amine and/or 4-dimethylaminopyridine.

For reductive amination reaction, use applicable reductive agent.Preferably, described reductive agent is selected from H ₂/ Pd/C, sodium borohydride, sodium cyanoborohydride and sodium triacetoxy borohydride.

According to the embodiment of reductive amination, (4-chloro-phenyl-) acetaldehyde of commercially available acquisition and allyl amine utilize H in reductive amination reacts ₂/ Pd/C reacts through reduction.Therefore, all parent materials for producing committed step intermediate 4 or 5 in direct mode all can easily obtain.

According to the embodiment of nucleophilic substitution, described leavings group is halogen or group-SO ₂r.

If described leavings group is halogen, then described halogen is most preferably bromine.Therefore, the present invention preferably utilize commercially available acquisition and the 4-chlorobenzene ethyl bromine that can easily obtain or allyl bromide 98 come to react with corresponding amine compound.Therefore, all parent materials producing committed step intermediate 4 or 5 in direct mode all can easily obtain.

In an especially preferred embodiment, 4-chlorobenzene ethyl bromine reacts when there is not solvent and other alkali with the allyl amine of at least 5 times of molar excess.Synthesis preferably includes the aftertreatment of at least step (c ') to (h '), and uses HCl in step (d '), thus obtains the compound of formula 5.

In another embodiment, excessive on a small quantity 4-chlorobenzene ethyl amine and allyl bromide 98 react in the tetrahydrofuran (THF) as solvent and the salt of wormwood as alkali.Synthesis preferably includes the aftertreatment of at least step (d ') to (h '), and uses HCl in step (d '), thus obtains the compound of formula 5.

If described leavings group is-OSO ₂r, then this group can in the presence of a base by corresponding alcohol and SULPHURYL CHLORIDE RSO ₂cl or acid anhydride (RSO ₂) ₂prepared by O, wherein R is with defined identical above.The sulfonic acid allyl ester of preferably not separating obtained sulfonic acid 4-chlorobenzene ethyl ester (formula A ') or gained (formula B '), but by its in single tank operation or original position be used in the step of preparation formula 4 compound or its salt, preferred formula 5 compound.

According to an embodiment, the sulfonic acid 4-chlorobenzene ethyl ester of formula A ' generates by making the phenylethyl alcohol of formula 7 and corresponding SULPHURYL CHLORIDE react in a solvent under inorganic or organic bases exist:

Wherein R is preferably methyl or 4-aminomethyl phenyl.Described alkali is preferably selected from tertiary amine such as triethylamine, diisopropyl ethyl amine and/or 4-dimethylaminopyridine.Described solvent is preferably selected from hydrochloric ether, aromatic hydrocarbon or pyridine, if wherein solvent is pyridine, does not then need other organic bases.

According to another embodiment, the sulfonic acid allyl ester of formula B ' generates by making vinyl carbinol and corresponding SULPHURYL CHLORIDE react in a solvent under inorganic or organic bases exist:

After reacting completely, described method optionally and preferably include the aftertreatment of previous step (b ') to (h ').

According to optional post-processing step (b '), if be that organic phase is extractible derived from the compound of described leavings group, then the reaction mixture obtained after can making compd A and B reaction with alkaline aqueous phase washing.Described alkaline aqueous phase be preferably selected from alkali bicarbonate, carbonate, phosphoric acid salt or oxyhydroxide the aqueous solution, be preferably selected from sodium carbonate or salt of wormwood.

According to post-processing step (c '), by evaporation removing volatile compound.

According to post-processing step (d '), the aqueous solution of inorganic salt is added in resistates, preferred sodium chloride solution, more preferably the sodium chloride solution of 10% (w/w) is to the sodium chloride solution (salt solution) of saturation concentration, and preferably add hydrochloric acid, thus obtain the compound of formula 5, wherein hydrochloric acid is preferably used with the aqueous solution form of 0.5-10 volumetric molar concentration.If only use the aqueous solution of inorganic salt in step (d '), do not use hydrochloric acid, then react the compound (free alkali) of production 4.Thus, required product is purified from water-soluble impurity.

According to post-processing step (e '), with with the not miscible solvent of water or solvent extraction product not miscible with salt solution, described is preferably selected from haloalkane and ester with the not miscible solvent of water, described with the not miscible solvent of salt solution such as C4-C5 alcohol, tetrahydrofuran (THF), acetonitrile, methyl ethyl ketone or methyl acetate, wherein methylene dichloride is most preferred Extraction solvent.

According to post-processing step (f '), except desolventizing is to obtain required product.If described method wishes the compound of production 4, complete aftertreatment by step (f '), thus obtain the oily product of formula 4.If described method wishes the compound of formula 4, the compound of preferred formula 5 that generate solid salt form, aftertreatment can proceed step (g ') and (h ').The purity of the crude product that step (f ') obtains can enough it can be used as parent material to be used in the step (A) of the method for first aspect of the present invention.If the purity of solid product should be increased, then therefore aftertreatment can proceed step (g ') and (h ').If the purity of the oiliness compound of formula 4 should be increased, then can apply common purification technique.

According to post-processing step (g '), crude product is suspended in applicable solvent.Described solvent is preferably acetone or isopropyl acetate.

According to post-processing step (h '), isolate solid product.The separation of product can be undertaken by any solid-liquid isolation technique, and described solid-liquid isolation technique is preferably selected from filtration or centrifugal.

According to an embodiment, described method can use any one in step (c ') to (h '), and optionally use (b ').

Hereinafter, illustrative summary (schema 7) of method of the present invention will be provided based on preferred, nonrestrictive experimental detail:

The racemic 8-of schema 7. chloro-1-methyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine (6) illustrative synthetic route

Sieve card XiLin hydrochloride and schema 2,4 and the prior art shown in 5 of the racemic formula 6 of the styroyl Intermediate Preparation by formula 2 or 3 of the present invention operate has compared two steps short.Those skilled in the art can select which embodiment of the present invention cause most economical from compound 2 or 3 and use purifying or the most economical route of the pharmaceutically acceptable product of preparation of thick formula 5 compound, or even select the shortest single tank operation, prerequisite is that described method does not substantially reduce total recovery at last purifying this is optimized on the one hand.

Hereinafter, by property by way of example, nonrestrictive embodiment describes the present invention in more detail.

experimental implementation

Embodiment 1: by 1-(2-bromotrifluoromethane)-4-chlorobenzene (3) synthesizing chlorinated N-(4-chlorobenzene ethyl) third-2-alkene-1-ammonium (5)

In the flask being equipped with magnetic stirring bar, put into allyl amine (31.0mL, 410mmol) and be heated to backflow.In 60 minutes, slowly add parent material (3,15g, 68mmol), reaction mixture is stirred under reflux and spends the night.Then solution be cooled to room temperature and be condensed into oily matter.This oily matter is distributed between methylene dichloride (100mL) and HCl1N (200mL)+salt solution (200mL).Separation of phases, by methylene dichloride (100mL) strip aqueous.By the methylene dichloride fraction dried over sodium sulfate merged, filter and concentrate.The solid of acquisition is suspended in isopropyl acetate (25mL), stirs 5 minutes and filter.Drying solid under vacuo, obtains white solid product 5 (12.6g, 80% yield), is used ¹h and IR analyzes and characterizes.

¹hNMR (500MHz, CDCl ₃, ppm) and δ 9.89 (bs, NH), 7.28 (d, J=8.5Hz, 2H), 7.18 (d, J=8.5Hz, 2H), 6.11 (m, 1H), 5.51 (d, J=17.0Hz, 1H), 5.48 (d, J=10.2Hz, 1H), 3.63 (d, J=7.0Hz, 2H), 3.23 (m, 2H), 3.13 (m, 2H); IR (pure): v=3436,2979,2942,2801,2765,2710,2641,2431,1495,1446,1425,1409,1339,1090,1016,994,944,835,806cm ^-1.

Embodiment 2: by 1-(2-amino-ethyl)-4-chlorobenzene (2) synthesizing chlorinated N-(4-chlorobenzene ethyl) third-2-alkene-1-ammonium (5):

The parent material (2,0.28mL, 2mmol) being dissolved in tetrahydrofuran (THF) (10mL) is put in the flask being equipped with magnetic stirring bar.Add salt of wormwood (0.55g, 4mmol) and allyl bromide 98 (0.165mL, 1.9mmol), reaction mixture is at room temperature stirred 18 hours.With water (20mL) and methylene dichloride (30mL) diluting reaction.Separation of phases, by methylene dichloride (20mL) strip aqueous.The methylene dichloride fraction the merged salt solution of 2/1 and the mixture of HCl1M are washed (2 × 30mL).By the sour phase that methylene dichloride (20mL) reextraction merges.Then, by the methylene dichloride fraction dried over sodium sulfate merged, filter and be condensed into solid.This solid to be suspended in acetone (5mL) and to filter, obtaining product 5 (35% yield).

Embodiment 3: by 1-(2-hydroxyethyl)-4-chlorobenzene (7) synthesizing chlorinated N-(4-chlorobenzene ethyl) third-2-alkene-1-ammonium (5):

The parent material (7,2mL, 11mmol) be dissolved in methylene dichloride (20mL) is loaded in the flask being equipped with magnetic stirring bar.Add triethylamine (1.84mL, 1.2eq), 4-dimethylaminopyridine (134mg, 0.1eq) and p-toluenesulfonyl chloride (2.3g, 1.1eq) successively.To add solution stirring 4 hours after allyl amine (3.3mL, 4eq), reaction is stirred under reflux and spends the night.Use saturated Na ₂cO ₃solution (30mL) washing reaction.Concentrated methylene dichloride phase, is dissolved in methylene dichloride (30mL) again by resistates, washed by the mixture (40mL) of solution with the salt solution/HCl1N of 2/1.By methylene dichloride (20mL) strip aqueous.By the methylene dichloride fraction Na of merging ₂sO ₄drying is also concentrated.Solid is suspended in isopropyl acetate (30mL), obtains crude product 5 (60% yield).

Embodiment 4: by chlorination N-(4-chlorobenzene ethyl) third-2-alkene-1-ammonium (5) synthesizing chlorinated 8-chloro-1-methyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -3- (6)

Parent material (5,232mg, 1mmol) is loaded in the flask being equipped with magnetic stirring bar.Add aluminum chloride (234mg, 1.75mmol) and stirring reaction.In 25 minutes, solid mixture is heated to 125 DEG C, then stirs 6 hours with the form melting phase at such a temperature.Solution is cooled to 90 DEG C, dilutes with salt solution (15mL).Solution is cooled further and uses methylene dichloride (2 × 20mL) to extract.By the methylene dichloride fraction dried over sodium sulfate merged, filter and concentrate, obtaining solid racemic sieve card XiLin hydrochloride (6,230mg; Chromatographic purity > 99%), used ¹hNMR spectrum carries out analyzing and confirming.

¹hNMR (500MHz, CDCl ₃) δ 10.2-9.80 (wide s, 2H), 7.26-7.19 (m, 2ArH), 7.08 (m, ArH), 3.82-3.45 (m, 4H), 3.15-2.80 (m, 3H), 1.45 (d, J=7.0Hz, 3H).

Embodiment 5: by chlorination N-(4-chlorobenzene ethyl) third-2-alkene-1-ammonium (5) synthesizing chlorinated 8-chloro-1-methyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -3- (6)

Parent material (5,232mg, 1mmol) is loaded in the flask being equipped with magnetic stirring bar.Add zinc chloride fine powder (238mg, 1.75mmol) and stirring reaction system.In 25 minutes, solid mixture is heated to 125 DEG C, then stirs 6 hours with the form melting phase at such a temperature.Solution be cooled to 90 DEG C and dilute with salt solution (15mL).Solution is cooled further and uses methylene dichloride (2 × 20mL) to extract.By the methylene dichloride fraction dried over sodium sulfate merged, filter and concentrate, obtaining sieve card XiLin hydrochloride (6,230mg of solid racemic; Chromatographic purity > 99.5%), as ¹hNMR spectrography confirmation, it corresponds to known compound.

Embodiment 6: by N-(4-chlorobenzene ethyl) third-2-alkene-1-amine (4) synthesizing chlorinated 8-chloro-1-methyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine -3-ammonium (6)

Parent material (4,224mg, 1.15mmol) is loaded in the flask being equipped with magnetic stirring bar.Add Aluminum chloride anhydrous (268mg, 2.0mmol) and stirring reaction system.In 25 minutes, solid mixture is heated to 125 DEG C, then stirs 6 hours with the form melting phase at such a temperature.Solution be cooled to 90 DEG C and dilute with salt solution (15mL).Solution is cooled further and extracts with methylene dichloride (2 × 20mL).By the methylene dichloride fraction dried over sodium sulfate merged, filter and concentrate, obtaining racemic sieve card XiLin hydrochloride (6,230mg of solid; Chromatographic purity > 99%), as ¹hNMR spectrography confirmation, it corresponds to known compound.

Claims

1. prepare 8-chloro-1-methyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepine of the formula 9 of the form of racemic object form, substantially enantiomer-pure or the form of enantiomer-pure or the method for its salt:

(A) compound of formula 4 is made:

The compound of its Chinese style 4 is preferably the form of solid salt, is preferably selected from hydrobromate or hydrochloride, and wherein this compound is most preferably the hydrochloride of formula 5:

And

Wherein said friedel-crafts reagent is preferably Lewis acid, it is preferably selected from transition metal and aluminum compound, more preferably zinc or aluminium salt is selected from, preferably salt hydrochlorate, and wherein most preferred Lewis acid is aluminum chloride, and wherein said friedel-crafts reagent, preferably described Lewis acid preferably with excessive molar weight, preferably with 1.1 to 10 times of molar excess, more preferably used with 1.25 to 2 times of molar excess.

2. method according to claim 1, wherein said method comprises following post-processing step:

B () is by being added to quencher reaction mixture in the aqueous solution of water or salt or salt mixture by hot melt, described reaction mixture is by making (when the there is not solvent) reaction under friedel-crafts reagent exists under pure condition of the compound or its salt of formula 4 obtain, wherein in step (b), preferably reaction mixture is cooled to the temperature that it remains liquid, preferably be cooled to 80-100 DEG C, more preferably 85-95 DEG C is cooled to, most preferably be cooled to 90 DEG C, and the quencher of use medium, wherein quench mixture is preferably the aqueous solution of inorganic salt, the preferably aqueous solution of sodium-chlor, its concentration is at least 5% (w/w), preferably 10% (w/w) is to saturated (salt solution), and/or

(c) by product from aqueous extraction to the not miscible solvent of water, wherein said be preferably selected from the not miscible solvent of water ether, ester, haloalkane, aromatics or the hydrocarbon of aliphatic series or its mixture, more preferably haloalkane and ester is selected from, and if use salt solution, but be also selected from and the miscible solvent not miscible with salt solution of pure water energy, such as C ₄-C ₅alcohol, tetrahydrofuran (THF) and acetonitrile, and wherein as being especially preferred with the not miscible methylene chloride of water; And/or

D () isolates the compound or its salt of formula 9;

And wherein said method preferably includes any one in step (b) to (d).

3. method according to claim 2,

(I) wherein in and by the reaction mixture of quencher after according to step (c) solvent extraction product not miscible with water; Or

(II) wherein in step (b), salt solution quencher reaction mixture is used, and wherein neutralize by the reaction mixture of quencher in step (c), but with the product of the hydrochloride form with the not miscible solvent of water, preferably dichloromethane extraction formula 6:

And wherein in step (d), pass through evaporation and not miscible this hydrochloride of separated from solvent of water, and wherein optionally by resistates solvent again suspendible or recrystallization, thus obtain product that is crystalline, purifying.

4. the method for Claims 2 or 3,

(I) in step (d), wherein to be gone out the compound of formula 9 with alkali (unhindered amina) isolated in form by evaporation and the not miscible solvent of water;

Or

(II) wherein by by the compound of formula 9 in solvent such as acetone or ether with the hydrochloride of HCl process by a converting compounds accepted way of doing sth 6 for formula 9, and wherein optionally by resistates solvent again suspendible or recrystallization, thus obtain product that is crystalline, purifying.

5. method as claimed in any of claims 1 to 4,

(I) racemic mixture of the compound or its salt of wherein said method production 9, the compound of preferred formula 6;

Or

(II) wherein said method is further comprising the steps of:

6. method as claimed in any of claims 1 to 5, described method is further comprising the steps of:

(A ') make compd A and B reaction:

Thus the compound or its salt of formula 4 is obtained in nucleophilic substitution reaction or in reductive amination reaction;

Wherein for the reaction of described reductive amination, use applicable reductive agent, be preferably selected from H ₂/ Pd/C, sodium borohydride, sodium cyanoborohydride and sodium triacetoxy borohydride; And

Wherein said method preferably includes following post-processing step:

(c ') is by evaporation removing volatile compound; And/or

(f ') is except desolventizing; And/or

7. method according to claim 6, it comprises any one in step (c ') to (h '), optionally comprise (b ').

8. the method according to claim 6 or 7,

(I) wherein said leavings group is bromine, and

Wherein preferably 4-chlorobenzene ethyl bromine reacts when there is not solvent and other alkali with the allyl amine of at least 5 times of molar excess, obtain the compound of formula 5, preferably obtain the compound of formula 5 at least step (c ') use HCl in step (d ') after to the process of (h '), or

Wherein preferably, 4-chlorobenzene ethyl amine excessive on a small quantity and allyl bromide 98 in as the tetrahydrofuran (THF) of solvent and as the salt of wormwood of alkali in react, obtain the compound of formula 5, preferably obtain the compound of formula 5 at least step (d ') use HCl in step (d ') after to the process of (h ');

Or

(II) wherein said leavings group is OSO ₂r, it can be prepared optionally by following methods: make corresponding alcohol and SULPHURYL CHLORIDE RSO ₂cl or acid anhydride (RSO ₂) ₂o reacts in the presence of a base, wherein R is with defined identical above, and the sulfonic acid allyl ester of wherein preferably not separating obtained sulfonic acid 4-chlorobenzene ethyl ester (formula A ') or gained (formula B '), but by its in the operation of single tank or original position be used in the step of the compound or its salt of preparation formula 4, the compound of preferred formula 5, and

Wherein preferably, the sulfonic acid 4-chlorobenzene ethyl ester of formula A ' is reacted by the styroyl alcohol of formula 7 and corresponding SULPHURYL CHLORIDE and produce under inorganic or organic bases exist, in a solvent:

Wherein R is preferably methyl or 4-aminomethyl phenyl, described inorganic or organic bases is preferably selected from tertiary amine such as triethylamine, diisopropyl ethyl amine and/or 4-dimethylaminopyridine, described solvent is preferably selected from hydrochloric ether, aromatic hydrocarbon or pyridine, if wherein solvent is pyridine, then do not need other organic bases, or

Wherein preferably, the sulfonic acid allyl ester of formula B ' is reacted by allyl alcohol and corresponding SULPHURYL CHLORIDE and produce under inorganic or organic bases exist, in a solvent:

Wherein R is preferably methyl or 4-aminomethyl phenyl, described inorganic or organic bases is preferably selected from tertiary amine such as triethylamine, diisopropyl ethyl amine and/or 4-dimethylaminopyridine, described solvent is preferably selected from hydrochloric ether, aromatic hydrocarbon or pyridine, if wherein solvent is pyridine, then do not need other organic bases.

9., according to the method in claim 6 or 7 described in any one, wherein allyl amine and (4-chloro-phenyl-) acetaldehyde react through reducing in reductive amination reacts, and preferably use H ₂/ Pd/C.

10. according to the method in claim 6 to 9 described in any one, the compound of its Chinese style 4 prepares according to the operation of step (A '), the operation of described step (A ') comprises at least step (b ') and, to (f '), and does not use HCl in step (d).

11. prepare enantiomer-pure substantially or the method for sieve card XiLin hydrochloride of formula 1 of enantiomer-pure:

Wherein said method

(I) carry out according to the following steps:

(A ') make compd A and B reaction,

(b ') optionally, with alkaline aqueous phase washing reaction mixture;

(c ') is by evaporation removing volatile compound;

(d ') adds the aqueous solution, preferably sodium chloride solution, more preferably 10% (w/w) sodium chloride solution of one or more inorganic salt to the sodium chloride solution (salt solution) of saturation concentration in resistates, and add hydrochloric acid, it is preferably used with the aqueous solution form of 0.5-10 volumetric molar concentration;

(f ') is except desolventizing;

(g ') suspendible resistates, is preferably suspended in resistates in acetone or isopropyl acetate;

The solid chemical compound of (h ') separate type 5;

D () isolates the compound of formula 6;

(e) converting compounds of formula 6 is become enantiomer-pure substantially or sieve card XiLin hydrochloride of formula 1 of enantiomer-pure, this conversion realizes by the following method: carry out chiral separation by the selective crystallization carrying out diastereomeric salt with resolution reagent, preferably tartrate, then carry out anionresin;

(II) carry out according to the following steps:

(A ') make compd A and B reaction,

(b ') optionally, with alkaline aqueous phase washing reaction mixture;

(c ') is by evaporation removing volatile compound;

(f ') is except desolventizing is to isolate thick formula 5 compound;

D () isolates the compound of formula 6;

(e) converting compounds of formula 6 is become enantiomer-pure substantially or sieve card XiLin hydrochloride of formula 1 of enantiomer-pure, this conversion realizes by the following method: carry out chiral separation by the selective crystallization carrying out diastereomeric salt with tartrate, then carry out anionresin;

Or

(III) carry out according to the following steps in single tank synthesis:

(A ') make compd A and B reaction,

F () isolates the compound of formula 6;

12. methods according to claim 11,

(I) wherein compd B is allyl amine, and wherein compd A is 4-chlorobenzene ethyl bromine;

Or

(II) wherein compd B is allyl bromide 98, and wherein compd A is 4-chlorobenzene ethyl amine.

The hydrochloride of N-allyl group-N-(4-chlorobenzene ethyl) amine of 13. formulas 5:

The hydrochloride of N-allyl group-N-(4-chlorobenzene ethyl) amine of N-allyl group-N-(4-chlorobenzene ethyl) amine of 14. formulas 4 or its salt, preferred formula 5 is for the preparation of the chloro-1-methyl-2 of 8-of racemic formula 9,3,4,5-tetrahydrochysene-1H-benzo [d] azepine or its salt, more preferably for the preparation of enantiomer-pure substantially or sieve card XiLin of enantiomer-pure or its salt, most preferably for the preparation of enantiomer-pure substantially or the purposes of sieve card XiLin hydrochloride of formula 1 of enantiomer-pure.

The method of the hydrochloride of N-allyl group-N-(4-chlorobenzene ethyl) amine of 15. preparation formulas 5:

Wherein said method comprises the following steps:

(A ') make compd A and B reaction:

Wherein said method preferably includes following post-processing step:

(c ') is by evaporation removing volatile compound; And/or

(d ') adds the aqueous solution, preferably sodium chloride solution, more preferably 10% (w/w) sodium chloride solution of one or more inorganic salt to the sodium chloride solution (salt solution) of saturation concentration in resistates, and add hydrochloric acid, it is preferably used with the aqueous solution form of 0.5-10 volumetric molar concentration; And/or

(f ') is except desolventizing; And/or

16. methods according to claim 15, it comprises any one in step (c ') to (h '), and optionally comprise (b ').

17. methods according to claim 15 or 16,

(I) wherein said leavings group is bromine, and

Wherein preferably, 4-chlorobenzene ethyl bromine reacts when there is not solvent and other alkali with the allyl amine of at least 5 times of molar excess, obtain the compound of formula 5, preferably obtain the compound of formula 5 at least step (c ') use HCl in step (d ') after to the process of (h '), or

Or

(II) wherein said leavings group is-OSO ₂r, it can be prepared optionally by following methods: make corresponding alcohol and SULPHURYL CHLORIDE RSO ₂cl or acid anhydride (RSO ₂) ₂o reacts in the presence of a base, wherein R is with defined identical above, and the sulfonic acid allyl ester of wherein preferably not separating obtained sulfonic acid 4-chlorobenzene ethyl ester (formula A ') or gained (formula B '), but by its in the operation of single tank or original position be used in the step of the compound of preparation formula 5, and

18. methods according to claim 15 or 16, wherein allyl amine and (4-chloro-phenyl-) acetaldehyde react through reducing in reductive amination reacts, and preferably use H ₂/ Pd/C.