CN101203521A - Process for the preparation of N,N'-disubstituted oxabispidines - Google Patents

Process for the preparation of N,N'-disubstituted oxabispidines Download PDF

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CN101203521A
CN101203521A CNA2006800222462A CN200680022246A CN101203521A CN 101203521 A CN101203521 A CN 101203521A CN A2006800222462 A CNA2006800222462 A CN A2006800222462A CN 200680022246 A CN200680022246 A CN 200680022246A CN 101203521 A CN101203521 A CN 101203521A
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alkyl
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D·克拉丁博尔
G·恩索
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AstraZeneca AB
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Abstract

There is provided a process for the preparation of a sulfonic acid salt of formula I, or a solvate thereof, which process comprises hydrogenating a sulfonic acid salt of formula II,. or a solvate thereof; in the presence of a solvent system consisting essentially of water, a C3-5 secondary alkyl alcohol and no more than 15% v/v of another organic solvent, wherein the sulfonic acid salt of formula I is optionally, without isolation, converted to a compound of formula IX, or a pharmaceutically-acceptable derivative thereof, wherein R<1>, R<2>, R<3>, R<6>, R<7>, R<8>, A, B and D have meanings given in the description.

Description

Preparation N, the method for the two pyridines of the dibasic oxa-of N'-
Invention field
The present invention relates to prepare N, the novel method of the two pyridines (oxabispidine) of N '-dibasic oxa-, one of them N-substituting group is (alkoxycarbonyl amino)-alkyl.
Background and prior art
In the preparation of medicinal substance, wish the cost minimum of preparation material, simultaneously, need to utilize the preparation approach that can satisfy modern environment and health and safety standard.
Improvement for the preparation approach that can cause total cost to reduce comprises:
(a) productive rate of the one or more steps of raising;
(b) reduce employed synthesis step and/or unit operation quantity;
(c) quantity of employed reagent of minimizing and/or solvent; And/or
(d) minimises power consumption (for example passing through elimination or reduction heating or refrigerative needs); And/or
(e) shorten the total time of finishing the requirement of preparation approach.
The ARR oxa-double pyridines compound that is used for the treatment of heart is described among the WO 01/028992.Disclosed in the literature compound is some N, the two pyridines of N '-dibasic oxa-, and one of them N-substituting group is 2-(alkoxycarbonyl amino) alkyl.The preparation approach of these compounds is described among WO 01/028992, WO 02/083690, WO 02/028864 and the WO 2004/035592.
In the above-mentioned document of mentioning, obtain target N, an approach of the two pyridines of N '-dibasic oxa-comprises the two pyridines of the mono-substituted oxa-of preparation.In some embodiment of this approach (for example, as described in WO 02/083690, WO 02/028864 and WO 2004/035592), the two pyridines of mono-substituted oxa-:
(i) have the N-substituting group, it is 2-(alkoxycarbonyl amino) alkyl; With
(ii) be to obtain by the deprotection that on another ring N-atom, has the two pyridines of oxa-of protecting group (for example benzyl).
In these embodiments, preparation target N, the final step of the two pyridines of N '-dibasic oxa-(the two pyridines of mono-substituted oxa-and second substituent coupling of N-) carries out under many different conditions.The definite character of institute's working conditions depends on the accurate feature that second substituent reactant of N-is provided especially, and applied single form that replaces the two pyridines of oxa-.
For example, carboxylamine tertiary butyl ester that WO 02/083690 has described is neutral [2-(9-oxa--3,7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-yl) ethyl] with comprise C 2Or C 3Various side chain couplings in the solvent system of alcohol (being ethanol or Virahol).Yet WO 2004/035592 has described the method for carrying out same conversion, but makes water as solvent and single 2,4 of the two pyridines of oxa-that replace of use as an alternative, and 6-trimethylbenzene sulfonate is as starting raw material.
The solvent that some method of describing among the WO 02/083690 (those methods that promptly comprise the alcoholic solution of preparation neutral [2-(9-oxa--3,7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-yl) ethyl] carboxylamine tertiary butyl ester) is used than the correlation method of WO 2004/035592 still less.On the other hand, the reagent that uses than the correlation method of WO 02/083690 of the method described of WO 2004/035592 (it preparation that comprises single sulfonate that replaces the two pyridines of oxa-with separate) still less.
Therefore, from the viewpoint of total cost minimum, described all methods of above-mentioned prior art have some relative defective.
The applicant has been surprised to find that the novel method of key intermediate in the preparation aforesaid method (being the two pyridines of mono-substituted oxa-), and this method comprises: at water and C 3-5Under the existence of secondary alkyl alcohol, with the sulfonate hydrogenation of the oxa-pair pyridines of N-(alkoxycarbonyl amino) alkyl-replacement of N '-protection.
Any above-mentioned prior art document be not both open had not advised that this method, this method provide especially than the method for WO 02/083690 yet and uses still less reagent and use the still less method of solvent than the method for WO 2004/035592.In addition, this novel method can provide the N that is more convenient for, the two pyridines of mono-substituted oxa-of the operation subsequently of the two pyridines of N '-dibasic oxa-.
Summary of the invention
According to first aspect of the present invention, the method for sulfonate or its solvate of preparation formula I is provided,
Figure S2006800222462D00021
R wherein 1Expression C 1-6Alkyl (optional) or aryl by the replacement of the substituting group of one or more being selected from-OH, halogen, cyano group, nitro and aryl;
D represents the C of optional branching 2-6Alkylidene group, condition are that it does not represent 1,1-C 2-6Alkylidene group;
R 2Represent unsubstituted C 1-4Alkyl, C 1-4Perfluoroalkyl or phenyl, the group of back is optional by one or more C that are selected from 1-6Alkyl, halogen, nitro and C 1-6The substituting group of alkoxyl group replaces; With
Wherein each aryl is optional the replacement, unless otherwise mentioned;
This method comprises: basically by water, C 3-5Secondary alkyl alcohol exists down with the solvent systems that the another kind of organic solvent that is no more than 15%v/v is formed, with sulfonate or its solvate hydrogenation of formula II,
Figure S2006800222462D00031
R wherein 3Expression is for the amino protecting group of destabilizing hydride, R 1, R 2With D as mentioned above,
This method is hereinafter to be referred as " the inventive method ".
Unless otherwise mentioned, alkyl defined herein and alkoxyl group can be straight chains, or when amount of carbon atom enough (being minimum three), can be side chain and/or cyclic.Further, when the quantity of carbon atom enough (being minimum four), this alkyl and alkoxyl group also can be part ring-types/acyclic.This alkyl and alkoxyl group also can be saturated, or when amount of carbon atom enough (being minimum two), can be undersaturated and/or by one or more oxygen and/or sulphur atom at interval.Unless otherwise mentioned, alkyl and alkoxyl group also can be by the particularly fluorine atom replacements of one or more halogens.
Unless otherwise mentioned, alkylidene group defined herein can be a straight chain, or when amount of carbon atom enough (being minimum two), can be side chain.This alkylidene chain also can be saturated, or when amount of carbon atom enough (being minimum two), can be undersaturated and/or by one or more oxygen and/or sulphur atom at interval.Yet, this alkylidene group preferably saturated and not at interval by any this heteroatoms.Alkylidene group also can be replaced by one or more halogen atoms, but still does not preferably have this replacement.
When using herein, term " aryl " comprises C 6-13Aryl (C for example 6-10) group.This group can be monocycle, dicyclo or trinucleated, and when being many rings, it can be all or part of aromatize.In this respect, the C that can mention 6-13Aryl comprises phenyl, naphthyl, 1,2,3,4-tetralyl, indanyl, indenyl, fluorenyl or the like.For fear of causing query, the substituent point of contact on the aryl can be any carbon atom by ring system.
Unless otherwise mentioned, aryl and aryloxy can be selected from following substituting group and replace by one or more :-OH, cyano group, halogen, nitro, C 1-6Alkyl, C 1-6Alkoxyl group ,-N (R 4a) R 4b,-C (O) R 4c,-C (O) OR 4d,-C (O) N (R 4e) R 4f,-N (R 4g) C (O) R 4h,-N (R 4i) S (O) 2R 5a,-S (O) 2N (R 4j) (R 4k) ,-S (O) 2R 5bAnd/or-OS (O) 2R 5c, (R wherein 4aTo R 4kRepresent H or C independently 1-6Alkyl, or R 4aAnd R 4bRepresent C together 3-6Alkylidene group (form four to seven yuan and contain azo-cycle), R 5aTo R 5cRepresent C independently 1-6Alkyl).When replacing, aryl is preferably replaced by the substituting group between one and three.
When this paper used, term " halogen " comprised fluorine, chlorine, bromine and iodine.
The compound that uses in this paper described method (those methods that promptly relate to the inventive method) or prepare by this paper described method can manifest tautomerism.Therefore, the inventive method comprises with any tautomeric form or with the mixture of any this form and uses or prepare this compound.
Similarly, the compound that adopts in this paper described method (those methods that promptly relate to the inventive method) or prepare by this paper described method also can contain one or more unsymmetrical carbons, and can therefore exist, and can manifest optical activity with enantiomorph or diastereo-isomerism volume morphing.Therefore, the inventive method comprises with any optics or diastereomeric form or with the mixture of any this form and uses or prepare this compound.
The solvate of formula I that can mention and II compound comprises hydrate (for example monohydrate).
Abbreviation is listed in the ending of this specification sheets.
Amino protecting group for destabilizing hydride it is known to the person skilled in the art that and be included in " Protective Groups in Organic Synthesis " third edition, T.W.Greene ﹠amp; P.G.M.Wutz, those groups of describing among the Wiley-Interscience (1999), particularly in the chapters and sections of " Protection for the Amino Group " by name, mention, this paper introduce in the document disclosure as a reference.This group comprise Cbz (carbobenzoxy-(Cbz)) group and-C (R 3a(R 3b)-aryl (R wherein 3aAnd R 3bRepresent C independently 1-6Alkyl (this alkyl is optional to be replaced by one or more-OH, halogen, cyano group, nitro and/or aryl) or preferred H), for example (benzyl) benzyl (for example (4-benzyl) benzyl) or especially optional by one or more (for example one to three) above about the benzyl of substituting group replacement mentioned in the substituting group on the aryl.
R 1Preferred meaning comprise C 1-6Alkyl, especially saturated C 1-6Alkyl.
R 1More preferably meaning comprise C 3-5Alkyl, especially saturated C 4Alkyl.
R 1Particularly preferred meaning comprise the tertiary butyl.
The preferred meaning of D comprises-(CH 2) 2-and-(CH 2) 3-.In a specific embodiments of the present invention, D represents-(CH 2) 2-.
R 2Preferred meaning comprise phenyl, optional be selected from C by one or more (for example one to three) 1-3The substituting group of alkyl (for example methyl), halogen and nitro (for example three substituting groups) replaces.
R 2More preferably meaning comprise the 4-chloro-phenyl-, or especially phenyl, aminomethyl phenyl (for example 4-aminomethyl phenyl) or trimethylphenyl (for example 2,4,6-trimethylphenyl).
Most preferably, the method for first aspect of the present invention is carried out on the salt of formula II, wherein R 3Expression benzyl (optional replaced, but most preferably replace) by aforesaid group.
Therefore preferred, carry out method according to first aspect of the present invention, so that the salt of formula Ia is provided,
R wherein 1As mentioned above.
In another embodiment, implement method according to first aspect of the present invention, so that the salt of formula Ib is provided,
Figure S2006800222462D00061
R wherein 1As mentioned above.
Method described herein (those methods that promptly relate to the inventive method) should not be in reactant or in case causes stereochemical change in the product that forms.
According to the hydrogenation of first aspect of the present invention, can utilize method known to those skilled in the art (for example using newborn hydrogen) to carry out, but preferably under catalytic condition, carry out (promptly in the presence of suitable catalyst, carrying out).
When using catalyzer to carry out hydrogenation, be preferably based on the catalyzer of rhodium, ruthenium or especially platinum metals (being nickel, platinum or particularly palladium).Catalyzer based on metal, can use powder type, as oxide compound or oxyhydroxide, or preferably be dispersed on the suitable carriers, for example charcoal, activated carbon or other carbon black.Preferably, catalyzer is palladium/charcoal (for example 3 to 10%Pd/C, particularly 5%Pd/C).
As mentioned above, be in the presence of solvent systems, to carry out according to the method for first aspect of the present invention, solvent systems is basically by water, C 3-5Secondary alkyl alcohol and the another kind of organic solvent that is no more than 15%v/v (for example be no more than 10,5,4,3,2 or especially 1%v/v) are formed.
Other organic solvent preferably is not a primary alconol, most preferred acid (for example acetic acid), or especially aprotic solvent (solvent that promptly lacks the OH group), for example methylene dichloride or toluene.
The organic solvent that can mention comprises in this respect: C 1-6Carboxylic acid; Two (C 1-6Alkyl) ether (two (C for example 1-4Alkyl) ether, for example ether); C 1-6Alkyl acetates (C for example 1-4Alkyl acetates, for example ethyl acetate); Chlorinated hydrocarbons (chlorination C for example 1-4Alkane is methylene dichloride for example, chloroform and tetracol phenixin); Hexane; Sherwood oil: aromatic hydrocarbons, for example benzene and single, two-or trialkyl benzene (for example sym-trimethylbenzene, dimethylbenzene, or toluene); With its mixture.
The C that can mention 3-5Secondary alkyl alcohol comprises C 3-4Secondary alkyl alcohol, for example second month in a season-butanols, isopropylcarbinol, or Virahol especially.
Under any circumstance, use water and C in the solvent systems 3-5The volumetric ratio of secondary alkyl alcohol can be any ratio from 5: 1 to 1: 10, preferably from any ratio of 2: 1 to 1: 7, more preferably from any ratio of 1: 1 to 1: 5, for example near 1: 3 or its.
Preferably, amount of solvents is between 1 and 4 relative volumes, for example between 1.5 and 2.5 (for example about 2) relative volume.
Hydrogenation can be carried out in atmosphere of hydrogen, both can environmental stress, also can be under high pressure (0.1MPa (1bar) at least for example, 0.2MPa (2bar) at least for example, preferably 0.3MPa (3bar) at least) carry out.Most preferably, hydrogenation is being carried out under any pressure of (for example 0.3 to 0.4MPa, promptly from 3 to 4bar) from 0.2 to 0.4MPa, for example under approximately 0.2MPa (2bar) or especially 0.35MPa (3.5bar).
Further, preferably at 5 ℃ or be higher than under 5 ℃ of (for example 10,15,20,25,30 or especially 35 ℃ or above temperature) temperature and carry out hydrogenation, any temperature of from 15 to 90 ℃ for example, for example from 20,25,30 or 35 to 75 ℃, or especially from 50 to 70 ℃ (for example at about 55 or 65 ℃).
Finish after the hydrogenation process according to first aspect of the present invention, can pass through the salt that standard technique (for example crystallization, evaporating solvent and/or filtration) is come separate type I.
In the particularly preferred embodiment of the present invention aspect first, directly carrying out hydrogenation (promptly not having under the situation of extra (additional) acid and/or alkali) on the sulfonate of formula II.
Can for example be described in those technology among International Patent Application WO 01/028992 and the WO 02/083690 according to the compound of technology preparation formula II well known by persons skilled in the art, this paper introduces its disclosure as a reference.
For example, the reaction of compound that the compound of formula II can be by formula III and the compound of formula IV prepares,
Figure S2006800222462D00071
R wherein 3As mentioned above,
Figure S2006800222462D00081
R wherein 1And R 2As mentioned above, reaction in organic solvent (for example toluene) is for example reacted under those conditions that WO 02/083690 describes.
Also can prepare the compound of formula III and IV according to technology well known by persons skilled in the art, for example be described in those technology among International Patent Application WO 01/028992 and the WO 02/083690.
For example, the compound of formula III can through type V compound or the cyclodehydration of (for example N-benzene sulfonyl or N-oil of mirbane sulphonyl (for example N-4-oil of mirbane sulphonyl)) derivative of its protection be used for preparation, wherein R 15As hereinbefore defined.
Figure S2006800222462D00082
Cyclisation can those conditions that WO for example 02/083690 describes (for example dewatering agent for example strong acid (for example methylsulfonic acid) and reactionlessness organic solvent (for example toluene) in the presence of) under carry out.
The formula III compound also can prepare according to known technique or with its similar techniques, for example formula VI compound (L wherein 1Represent suitable leavings group (for example halogen, for example iodine), R 3As mentioned above) with the derivative (for example benzylamine) of ammonia or its protection in for example Chem.Ber.96 (11), react under 2827 (1963) those conditions of describing.
Figure S2006800222462D00083
Formula IV compound can through type VII respective compound (R wherein 1With D as hereinbefore defined) with formula VIII compound (L wherein 2Expression leavings group (for example halogen, for example chlorine), R 2As hereinbefore defined) for example under those reaction conditionss that WO for example 02/083690 describes, react and prepare.
Figure S2006800222462D00091
R 2-S(O) 2-L 2 VIII
The compound of formula V, V, VI, VII and VIII and its derivative, both can commercial buy, in the literature known (for example the preparation of formula V and VI compound is described among the WO 02/083690), also can be according to known technology, use suitable reagent and reaction conditions, obtain by conventional synthetic method by the starting raw material that obtains easily.
As noted before, if necessary, the sulfonate of formula I can be separated, and choose wantonly and utilize technology well known by persons skilled in the art to be further purified.Yet in particularly preferred embodiment of the present invention, the salt of separate type I not promptly need not separate it or removes and just can further process from the solvent systems for preparing it.
Therefore, preferably carry out method, so that basically by water, C according to first aspect of the present invention 3-5The salts solution of formula I is provided in the solvent systems of secondary alkyl alcohol and the another kind of organic solvent composition that is no more than 20% (for example being no more than 15 or particularly 10 or 5%) v/v.
In this embodiment, preferred solvent system comprises as mentioned above those, for example basically by water, Virahol be no more than the solvent systems that the another kind of organic solvent of 15%v/v is formed.
When the salt of separate type I not (as mentioned above), solvent systems (salt of formula I is present in wherein) can and the salt of formula I and provide the couling process between N '-substituent molecule to adapt.In this case, compare with the method for description of the Prior Art, prepare resulting N, the method for the two pyridines (by the compound of formula II) of N '-dibasic oxa-is effective especially.
In this respect, and, provide the method for preparation formula IX compound or its pharmacy acceptable derivates according to a second aspect of the present invention;
Figure S2006800222462D00101
R wherein 1With D as hereinbefore defined;
R 6Expression H, halogen, C 1-6Alkyl ,-OR 9,-E-N (R 10) R 11, or and R 7Expression=O together;
R 7Expression H, C 1-6Alkyl or and R 6Together, expression=O;
R 9Expression H, C 1-6Alkyl ,-the E-aryl ,-E-Het 1,-C (O) R 12a,-C (O) OR 12bOr-C (O) N (R 13a) R 13b
R 10Expression H, C 1-6Alkyl ,-the E-aryl ,-E-Het 1,-C (O) R 12a,-C (O) OR 12b,-S (O) 2R 12cC ,-[(O)] pN (R 13a) R 13bOr-C (NH) NH 2
R 11Expression H, C 1-6Alkyl ,-the E-aryl or-C (O) R 12d
When using herein, R 12aTo R 12dWhen occurring, represent C independently at every turn 1-6Alkyl is (optional by one or more halogen, aryl and Het of being selected from 2Substituting group replace), aryl, Het 3Or R 12aAnd R 12dRepresent H independently;
When using herein, R 13aAnd R 13bWhen occurring, represent H or C independently at every turn 1-6Alkyl is (optional by one or more halogen, aryl and Het of being selected from 4Substituting group replace), aryl, Het 5, or represent C together 3-6Alkylidene group, optional by the O atomic separation;
When using herein, E represents direct key or C at every turn when occurring 1-4Alkylidene group;
P represents 1 or 2;
A represent direct key ,-J-,-J-N (R 14a)-,-J-S (O) 2N (R 14b)-,-J-N (R 14c) S (O) 2-or-J-O-(in four groups of back ,-J is connected with the two pyridine ring nitrogen of oxa-);
B represents-Z-{[C (O)] aC (H) (R 15a) b-,-Z-[C (O)] cN (R 15b)-,-Z-N (R 15c) S (O) 2-,-Z-S (O) 2N (R 15d)-,-Z-S (O) n-,-Z-O-(in six groups of back, Z and have R 6And R 7Carbon atom be connected) ,-N (R 15e)-Z-,-N (R 15f) S (O) 2-Z-,-S (O) 2N (R 15g)-Z-or-N (R 15h) C (O) O-Z-(in four groups of back, Z and R 8Group is connected);
J represents C 1-6Alkylidene group, optional quilt-S (O) 2N (R 14d)-or-N (R 14e) S (O) 2-at interval, and/or optional by one or more being selected from-OH, halogen and amino substituting group replacement;
Z represents direct key or C 1-4Alkylidene group, optional quilt-N (R 15i) S (O) 2-or-S (O) 2N (R 15j)-at interval;
A, b and c represent 0 or 1 independently;
N represents 0,1 or 2;
When using herein, R 14aTo R 14eWhen occurring, represent H or C independently at every turn 1-6Alkyl;
R 15aExpression H, or and R 8Single ortho-substituent on the group (ortho position-connect with respect to the B group position) together, R 15aExpression C 2-4Alkylidene group, it is optional by O, S, N (H) or N (C 1-6Alkyl) at interval or be terminal;
R 15bExpression H, C 1-6Alkyl or and R 8Single ortho-substituent on the group (ortho position-connect with respect to the B group position) together, R 15bExpression C 2-4Alkylidene group;
When using herein, R15c to R15j represents H or C at every turn independently when occurring 1-6Alkyl;
R 8Expression phenyl or pyridyl, wherein two groups all choose by one or more and are selected from following substituting group replacement :-OH, cyano group, halogen, nitro, C 1-6Alkyl (optional quilt-N (H) C (O) OR 16aBe terminal), C 1-6Alkoxyl group ,-N (R 17a) R 17b,-C (O) R 17c,-C (O) OR 17d,-C (O) N (R 17e) R 17f,-N (R 17g) C (O) R 17h,-N (R 17i) C (O) N (R 17j) R 17k,-N (R 17m) S (O) 2R 16b,-S (O) 2N (R 17n) R 16o,-S (O) 2R 16c,-OS (O) 2R 16dAnd/or aryl;
And ortho-substituent (ortho position-with respect to the tie point of B) can
(i) and R 15aRepresent C together 2-4Alkylidene group, it is optional by O, S, N (H) or N (C 1-6Alkyl) at interval or be terminal, or
(ii) with R 15bRepresent C together 2-4Alkylidene group;
R 16aTo R 16dRepresent C independently 1-6Alkyl;
R 17aAnd R 17bRepresent H, C independently 1-6Alkyl, or represent C together 3-6Alkylidene group forms four to seven yuan and contains azo-cycle;
R 17cTo R 17oRepresent H or C independently 1-6Alkyl; With
When using herein, Het 1To Het 5When occurring, represent 5 to 12 yuan of heterocyclic groups independently at every turn, this heterocyclic group contains one or more heteroatomss that are selected from oxygen, nitrogen and/or sulphur, and this heterocyclic group is optional to be selected from following substituting group and to replace by one or more :=O ,-OH, cyano group, halogen, nitro, C 1-6Alkyl, C 1-6Alkoxyl group, aryl, aryloxy ,-N (R 18a) R 18b,-C (O) R 18c,-C (O) OR 18d,-C (O) N (R 18e) R 18f,-N (R 18g) C (O) R 18h,-S (O) 2N (R 18i) (R 18j) and/or-N (R 18k) S (O) 2R 18l
R 18aTo R 18lRepresent C independently 1-6Alkyl, aryl or R 18aTo R 18kRepresent H independently;
Condition is:
(a) work as R 7Expression H or C 1-6Alkyl; And A represents-J-N (R 14a)-or-during J-O-, so:
(i) J does not represent C 1Alkylidene group or 1,1-C 2-6Alkylidene group; With
(ii) B does not represent-N (R 15b)-,-N (R 15c) S (O) 2-,-S (O) n-,-O-,-N (R 15e)-Z ,-N (R 15f) S (O) 2-Z-or-N (R 15h) C (O) O-Z-; With
(b) work as R 2Expression-OR 9Or-E-N (R 10) R 11When (wherein E represents direct key), so:
(i) A do not represent direct key ,-J-N (R 14a)-,-J-S (O) 2-N (R 14b)-or-J-O-; With
(ii) B does not represent-N (R 15b)-,-N (R 15c) S (O) 2-,-S (O) n-,-O-,-N (R 15e)-Z ,-N (R 15f) S (O) 2-Z-or-N (R 15h) C (O) O-Z-; With
(c) represent-J-N (R as A 14c) S (O) 2In-time, J does not represent C so 1Alkylidene group or 1,1-C 2-6Alkylidene group; With
(d) work as R 3Expression H or C 1-6Alkyl and A represent-J-S (O) 2N (R 14b)-time, B does not represent-N (R so 15b)-,-N (R 15c) S (O) 2-,-S (O) n-,-O-,-N (R 15e)-Z-,-N (R 15f) S (O) 2-Z-or-N (R 15h) C (O) O-Z-; With
Wherein each aryl and aryloxy are optional the replacements, unless otherwise mentioned;
This method comprises:
(I) basically by water, C 3-5Secondary alkyl alcohol exists down with the solvent systems that the another kind of organic solvent that is no more than 15%v/v is formed, with sulfonate or its solvate hydrogenation of formula II,
Figure S2006800222462D00121
R wherein 1, R 2, R 3With D as mentioned above and
(II) it need not be separated, make the sulfonate of the formula I that forms thus,
Figure S2006800222462D00131
R wherein 1With D as hereinbefore defined,
With alkali and
(a) compound of formula X reaction,
Figure S2006800222462D00132
L wherein 3Expression leavings group (for example methanesulfonates, tosylate, sym-toluenesulfonic acid ester or halogen), R 6, R 7, R 8, A and B as hereinbefore defined, or
(b) for the compound of formula IX, wherein A represents C 2Alkylidene group, R 2And R 3Expression=O group together, with the compound reaction of formula XI,
Figure S2006800222462D00133
R wherein 8With B as hereinbefore defined, or
(c) for the compound of formula IX, wherein A represents CH 2, R 6Expression-OH or-N (H) R 10, with the compound reaction of formula XII,
Wherein Y represent-O-or-NR 10-, R 6, R 8, R 10With B as hereinbefore defined,
Wherein the reaction with formula X, XI or XII is to comprise water and C 3-5Carry out under the existence of the solvent systems of secondary alkyl alcohol,
This also is called for short " the inventive method " below method.
For " need not separate ", we are meant that the salt (it is as intermediate) of formula I need not (be that system is basically by water, C with solvent systems (it forms therein) 3-5Secondary alkyl alcohol is formed with the another kind of organic solvent that is no more than 15%v/v) separate.
In this respect, term " need not separate " and comprises wherein at least 10% in (for example at least 20,30,40,50,60,70,80,90 or particularly 95%) above-mentioned steps (I) solvent that uses and is brought in the above-mentioned steps (II) also the process of use therein.Therefore, partial solvent system all or that preferably use above-mentioned steps (II) can be provided (is that the solvent system comprises water and C to the solvent mixture that changes over to from above-mentioned steps (I) 3-5Secondary alkyl alcohol).
When this paper used, term " aryloxy " comprised C 6-13Aryloxy, phenoxy group for example, naphthyloxy, fluorenes oxygen base or the like.For fear of causing query, the aryloxy that relates to herein is that the O-atom of logical peroxy is connected with the rest part of molecule.
Unless otherwise mentioned, aryloxy can be selected from following substituting group and replace by one or more :-OH, cyano group, halogen, nitro, C 1-6Alkyl, C 1-6Alkoxyl group ,-N (R 4a) R 4b,-C (O) R 4c,-C (O) OR 4d,-C (O) N (R 4e) R 4f,-N (R 4g) C (O) R 4h,-N (R 4i) S (O) 2R 5a,-S (O) 2N (R 4j) (R 4k) ,-S (O) 2R 5bAnd/or-OS (O) 2R 5c, (R wherein 4aTo R 4k, R 5aTo R 5cAs hereinbefore defined).When replacing, aryloxy is preferably replaced by the substituting group between one and three.
Het (the Het that can mention 1, Het 2, Het 3, Het 4And Het 5) group comprises and contain 1 to 4 heteroatoms (being selected from group oxygen, nitrogen and/or sulphur) and total atom number those groups between 5 and 12 of ring system wherein.Het (Het 1, Het 2, Het 3, Het 4And Het 5) group can be saturated fully, whole aromatize, part aromatize and/or dicyclo in nature.The heterocyclic group that can mention comprises: 1-azabicyclo [2.2.2] octyl group, benzimidazolyl-, benzisoxa  azoles base, benzo two  alkyl, benzo Dioxepane base (benzodioxepanyl), benzo dioxolyl (benzodioxolyl), benzofuryl, benzo furazan base, benzo morpholinyl, 2,1,3-benzo  di azoly, benzoxazine ketone group, benzoxazol alkyl, benzoxazol base, the benzopyrazoles base, benzo [e] pyrimidine, 2,1,3-diazosulfide base, benzothiazolyl, benzothienyl, benzotriazole base, chromanyl, chromenyl, cinnolines base, 2,3-dihydrobenzo imidazolyl, 2,3-dihydrobenzo [b] furyl, 1,3-dihydrobenzo [c] furyl, 2, the 3-pyrrolin is [2,3-b] pyridyl also, two  alkyl, furyl, hexahydropyrimidine base, glycolylurea base, imidazolyl, imidazo [1,2-a] pyridyl, imidazo [2,3-b] thiazolyl, indyl, isoquinolyl, different  azoles base, maleimide base, morpholinyl,  di azoly, 1,3- piperazine base,  azoles base, phthalazinyl, piperazinyl, piperidyl, purine radicals, pyranyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidyl, pyrrolidone-base, pyrrolidyl, pyrrolinyl, pyrrolo-[2,3-b] pyridyl, pyrrolo-[5,1-b] pyridyl, pyrrolo-[2,3-c] pyridyl, pyrryl, quinazolyl, quinolyl, tetramethylene sulfone base (sulfolanyl), 3-sulfolenyl, 4,5,6,7-tetrahydrochysene phenylimidazole base, 4,5,6,7-tetrahydro benzo pyrazolyl, 5,6,7,8-tetrahydro benzo [e] pyrimidine, tetrahydrofuran base, THP trtrahydropyranyl, 3,4,5, the 6-tetrahydro pyridyl, 1,2,3,4-tetrahydro-pyrimidine base, 3,4,5,6-tetrahydrochysene-pyrimidyl, thiadiazolyl group, thiazolidyl, thiazolyl, thienyl, thieno-[5,1-c] pyridyl, the sulfo-chromanyl, triazolyl, 1,3,4-triazolo [2,3-b] pyrimidyl or the like.
If suitable, Het (Het 1, Het 2, Het 3, Het 4And Het 5) on substituting group can be arranged on any atom of ring system, comprise heteroatoms.Het (Het 1, Het 2, Het 3, Het 4And Het 5) point of contact of group can comprise (if suitable) heteroatoms by any atom in the ring system, or the atom on any fused iso that can exist with part ring system form.Het (Het 1, Het 2, Het 3, Het 4And Het 5) group also can be N-or S-oxidised form.
The pharmacy acceptable derivates of formula IX compound comprises salt and solvate.The salt that can mention comprises acid salt.
The pharmacy acceptable derivates of formula IX compound is also included within on the two pyridines of oxa-or (works as R 8Expression is during pyridyl) C on pyridyl nitrogen 1-4Alkyl quaternary ammonium salts and N-oxide compound, condition are, when having the N-oxide compound:
(a) Het (Het 1, Het 2, Het 3, Het 4And Het 5) group do not comprise unoxidized S-atom; And/or
(b) represent-Z-S (O) as B nIn-time, n does not represent 0.
Preferred formula IX compound comprises following compounds, wherein:
R 1Expression C 1-6Alkyl, particularly saturated C 1-6Alkyl;
R 6Expression H, halogen, C 1-3Alkyl ,-OR 9,-N (H) R 10, or and R 7Expression=O together;
R 7Expression H, C 1-3Alkyl or and R 6Together, expression=O;
R 9Expression H, C 1-6Alkyl ,-E-(optional replace phenyl) or-E-Het 1
R 10Expression H, C 1-6Alkyl ,-E-(the optional phenyl that replaces) ,-C (O) R 12a,-C (O) OR 12b, S (O) 2R 12c,-C (O) N (R 13a) R 13bOr-C (NH) NH 2
R 12aTo R 12cRepresent C independently 1-6Alkyl, or R 12aExpression H;
R 13aAnd R 13bRepresent H or C independently 1-4Alkyl;
When using herein, E represents direct key or C at every turn when occurring 1-2Alkylidene group;
A represents-J-,-J-N (R 14a)-or-J-O-;
B represents-Z-,-Z-N (R 15b)-,-Z-S (O) n-or-Z-O-;
J represents C 1-4Alkylidene group;
Z represents direct key or C 1-3Alkylidene group;
R 14aAnd R 15bRepresent H or C independently 1-4Alkyl;
N represents 0 or 2;
R 4Expression phenyl or pyridyl, two groups all choose by one or more and are selected from following substituting group replacement: cyano group, halogen, nitro, C 1-6Alkyl, C 1-6Alkoxyl group ,-NH 2,-C (O) N (R 17e) R 17f,-N (R 17g) C (O) R 17hWith-N (R 17m) S (O) 2-R 16b
R 16bExpression C 1-3Alkyl
When using herein, R 17eTo R 17mWhen occurring, represent H or C independently at every turn 1-4Alkyl;
Het 1To Het 5Optional be selected from following substituting group and replace :=O, cyano group, halogen, nitro, C by one or more 1-4Alkyl, C 1-4Alkoxyl group ,-N (R 18a) R 18b,-C (O) R 18cAnd C (O) OR 18d
R 18aTo R 18dRepresent H, C independently 1-4Alkyl or aryl;
R represents-(CH 2) 2-;
Optional substituting group on aryl and the aryloxy is one or more following substituting groups that are selected from: cyano group, halogen, nitro, C 1-4Alkyl and C 1-4Alkoxyl group, except as otherwise noted.
Further preferred formula IX compound comprises following compounds, wherein:
R 1Expression C 3-5Alkyl, particularly saturated C 4Alkyl;
R 6Expression H, methyl ,-OR 9Or-N (H) R 10
R 7Expression H or methyl;
R 9Expression H, C 1-2(this phenyl is optional by one or more cyano group and C of being selected from for alkyl or phenyl 1-4The substituting group of alkoxyl group replaces);
R 10Expression H, C 1-2(this phenyl is optional by one or more cyano group, halogen, nitro, C of being selected from for alkyl, phenyl 1-4Alkyl and C 1-4The substituting group of alkoxyl group replaces) ,-C (O)-R 12aOr-C (O) O-R 12b
R 12aAnd R 12bRepresent C independently 1-6Alkyl;
A represents C 1-4Alkylidene group;
B represents-Z-,-Z-N (R 15b)-,-Z-S (O) 2-or-Z-O-;
R 15bExpression H or methyl;
R 8Expression pyridyl or phenyl, the group of back is optional to be selected from following substituting group replacement by one to three: cyano group, nitro, C 1-2Alkoxyl group, NH 2With-N (H) S (O) 2CH 3
Also further preferred formula IX compound comprises following compounds, wherein:
R 6Expression H ,-OR 9Or-N (H) R 10
R 9(this phenyl is optional by one or more cyano group and C of being selected from for expression H or phenyl 1-2The substituting group of alkoxyl group replaces);
R 10Expression H, phenyl (optional replaced) by one or more cyano group or-C (O) O-C 1-5Alkyl;
A represents C 1-3Alkylidene group;
B represents-Z-,-Z-N (H)-,-Z-S (O) 2-or-Z-O-;
R 8Be illustrated in the phenyl that is replaced by cyano group with respect to the ortho position of B and/or particularly contraposition.
Particularly preferred formula IX compound comprises:
R 1The expression tertiary butyl;
R 6The expression H or-OH;
R 7Expression H;
A represents CH 2
B represents-Z-,-Z-N (H)-or-Z-O-;
Z represents direct key or C 1-2Alkylidene group;
R 8Expression is to cyano-phenyl.
Particularly preferred formula IX compound comprises the structure fragment of its Chinese style IXa
Figure S2006800222462D00171
Represent following those:
Figure S2006800222462D00181
In further embodiment of the present invention, the compound of the formula IX that can mention comprises following compounds, wherein:
R 1The expression tertiary butyl;
D represents-(CH 2) 2-or-(CH 2) 3-;
R 6The expression H or-OH;
R 7Expression H;
A represents CH 2
B represents-Z-O-;
Z represents direct key or C 1-2Alkylidene group (for example, CH 2);
R 8Be illustrated in that contraposition (with respect to B) is replaced by cyano group and at the ortho position (with respect to B) by the optional phenyl that replaces of fluorine.
About this further embodiment of the present invention, the formula IX compound that can mention comprises the structure fragment of its Chinese style IXa
Figure S2006800222462D00182
Represent following those:
Figure S2006800222462D00191
Therefore, the concrete formula IX compound that can mention comprises:
2-{7-[(2S)-3-(4-cyano-benzene oxygen)-2-hydroxypropyl]-9-oxa--3,7-diaza-two ring [3.3.1] ninth of the ten Heavenly Stems-3-yl } the ethyl carbamic acid tertiary butyl ester;
(2-{7-[2-(4-cyano group-2-fluorophenoxy) ethyl]-9-oxa--3,7-diazabicyclo-[3.3.1] ninth of the ten Heavenly Stems-3-yl } ethyl) the carboxylamine tertiary butyl ester;
(3-{7-[3-(4-cyano-benzene oxygen) propyl group]-9-oxa--3,7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-yl } propyl group) the carboxylamine tertiary butyl ester,
With its salt and/or solvate.
For method according to second aspect of the present invention, the salt of preferred formula II comprise above about according to the method for first aspect of the present invention defined those.
For temperature, solvent systems and the hydrogenation conditions of top step (I), preferably include above about according to the method for first aspect of the present invention defined those.
As mentioned above, the solvent systems that is used for top step (II) comprises water and C 3-5Secondary alkyl alcohol.The preferred solvent systems of step (II) comprises basically by water, C 3-5Secondary alkyl alcohol and be no more than those solvent systemss that the another kind of organic solvent of 20%v/v (for example be no more than 15,10 or particularly 5%v/v) is formed.
In this respect, above the organic solvent that can mention comprises about according to the mentioned organic solvent of the method for first aspect of the present invention.The concrete solvent that can mention is a toluene.It will be understood to those of skill in the art that the R in the salt of formula II 3Be under the situation of benzyl, toluene is the hydrogenated products of top step (I), (may reside in thus in the solvent systems that changes top step (II) over to).
Further, when organic solvent is acid, it will be understood to those of skill in the art that, before the compound reaction of the salt of formula I and formula X, XI or XII or simultaneously, this acid (by adding alkali, for example following a kind of about in those alkali of touching upon according to the method for second aspect present invention) may need to neutralize.
When using catalyzer in the hydrogenation of step (I), the mixture that obtains after preferably step (I) being finished basically then filters, and removes catalyzer, then mixture is directly used in the step (II) in the above.
Preferably, top step (II), be the reaction between the compound of the salt of formula I and formula X, XI or XII, initial by coming in the mixture that the salt of formula I (above being dissolved in about according in the mentioned solvent systems of the method for first aspect of the present invention) is joined alkali and formula X, XI or XII compound.In this embodiment, preferably formula X, XI or XII compound and alkali are pre-mixed (for example solvent-free solid or oil form).
In another embodiment, reaction between the salt of formula I and formula X, XI or the XII compound, be come in the mixture (above being dissolved in about according in the mentioned solvent systems of the method for first aspect of the present invention) by formula X, XI or XII compound being joined the salt of alkali and formula I initial.
Alkali can use with solid form, or preferably uses with aqueous solution form.Alkali can be alkali metal hydrocarbonate, alkali metal hydroxide and/or particularly alkaline carbonate (for example salt of wormwood or particularly yellow soda ash).
When employed alkali was aqueous solution form, volumetric molar concentration was in 0.1 to 5M scope so, preferably 0.1 and 3M between, about 0.3M for example.
Preferably, during the quantity of the alkali that uses is enough to and the salt (promptly discharging corresponding neutral amine) of formula I, (for example with X compound reaction) if necessary, any acid that reaction produced of the top step (II) that is enough to neutralize.Therefore, alkali is merely hit and the salt of formula I if desired, and usage quantity should be at least and the moles such as usage quantity of the salt of formula I.Further, if require in the alkali and the salt of formula I and the acid that top step (II) produced between the reaction period, compare with the quantity of the salt of use formula I so, usage quantity should show at least two molar equivalents.
When using two alkali cpds (for example salt of wormwood or particularly yellow soda ash) as alkali, the stoichiometric ratio of alkali and formula I compound is 2: 1 to 1: 5 scope so, preferably between 1: 1 and 1: 3, for example near 1: 2 or its.
The reaction of step preferably, (II) is the reaction between the salt of formula I and formula XII compound.In this respect, particularly preferred formula XII compound comprises 4-(epoxy ethyl methoxyl group) benzonitrile, for example 4-[(2S)-epoxy ethyl-methoxyl group] benzonitrile.
In another embodiment of the invention, the reaction of step (II) is between the compound of the salt of formula I and formula X.In this respect, the formula X compound that can mention comprises wherein R 6To R 8, A and B as mentioned above, L 3Those compounds of expression sym-toluenesulfonic acid ester or particularly tosylate or halogen (for example bromine).The concrete formula X compound that can mention comprises 4-(2-bromine oxethyl)-3-fluoro benzonitrile and 2-(4-cyano group-2-fluorophenoxy) ethyltoluene-4-sulphonate.
Above formula XII compound is used for during the reaction of step (II), then the stoichiometric ratio of formula I compound and formula XII compound is 3: 2 to 2: 3 scope, for example near 1: 1 or its.
With the reaction of formula X, XI or XII compound can be in envrionment temperature or preferably carry out at elevated temperatures, any temperature of from 30 to 120 ℃ (for example from 60 to 110 ℃) for example.The C of the partial solvent system of step (II) above being used as 3-5When secondary alkyl alcohol was Virahol, reaction was preferably carried out under about 78 ℃ so.
When the salt of formula I and the reaction between formula X, XI or the XII compound are finished basically, so can be by the compound of following method separate type IX:
(a) by distilling all pure components of removing basically in the solvent systems;
(b) add and the immiscible organic solvent of water;
(c) after the adding, wash organic solvent with alkali aqueous solution;
(d) formula I compound is extracted the aqueous acid from the organic phase that obtains;
(e) aqueous acidic that obtains is alkalized mutually, and formula I compound is extracted in the alcoholic solvent (with concentrated sodium chloride aqueous solution unmixing); With
(f) with the crystallization and separating from alcoholic solvent of formula I compound.
It will be understood to those of skill in the art that step (a) can be carried out the separation of immiscible solvent phase in (f) if suitable in the above.
The distillation that can carry out during aftertreatment (referring to step (a) above for example) can be carried out under decompression and/or the temperature (for example between 25 and 110 ℃) that is raising.
The non-water that uses in the step (b) representative examples of organic of can dissolving each other comprises in the above: two (C 1-6Alkyl) ether (two (C for example 1-4Alkyl) ether, for example ether and diisopropyl ether), C 1-6Alkyl acetates (C for example 1-4Alkyl acetates, for example ethyl acetate), chlorinated hydrocarbons (chlorination C for example 1-4Alkane is methylene dichloride for example, chloroform and tetracol phenixin), hexane, sherwood oil and aromatic hydrocarbons, for example benzene and single, two-or trialkyl benzene (for example sym-trimethylbenzene, dimethylbenzene, or toluene).Operable preferred organic solvent comprises aromatize solvent (for example benzene or particularly toluene) and two (C 1-4Alkyl) ether (for example diisopropyl ether).This organic solvent can be in aftertreatment, use at elevated temperatures.
It will be understood to those of skill in the art that if the boiling point ratio of the organic solvent that top (b) uses is used for solvent systems that the inventive method is used and (promptly comprise water and C 3-5The mixture of secondary alkyl alcohol) boiling point height, step (a) and (b) can put upside down, or step (b) can be carried out before and afterwards at step (a).For example, when the mixture of water and Virahol be used for the inventive method and toluene be used for above during step (b), can before the mixture that remove (by distillation) water and Virahol, add so.
The example that can be used for the alkali aqueous solution of top step (c) comprises alkali metal hydroxide (for example sodium hydroxide).Can carry out neutralizing treatment (top step (c)), so that from product mixtures, remove sym-toluenesulfonic acid.
Preferably, the acid of using in the above-mentioned steps (d) is weak acid and/or water soluble acid, be especially weak acid also be water soluble acid.
When using herein, term " weak, water soluble acid " comprising: have 1 mg/ml or bigger solvability and have those acid of the pKa (measuring) between 2 and 7 (preferably between 3 and 5) in water in water.In this respect, preferred, the water-soluble weak acid that can mention comprises for example acetate of carboxylic acid, or citric acid especially.
Sour usage quantity in (d) in the above, preferably be enough to from organic phase basically all formula I compounds extract aqueous acidic mutually (for example, with the equimolar quantity of formula I compound quantity).So, can use the extraction of step (d), to remove non-alkaline impurities.
Comprise 4-methyl-2--amylalcohol, propyl carbinol, the second month in a season-butanols and n-hexyl alcohol with the immiscible alcoholic solvent of the concentrated sodium chloride aqueous solution (and using in the step (e)) in the above.
For " the concentrated sodium chloride aqueous solution ", we refer to and comprise and have 5 and 35 the sodium chloride aqueous solution of weight percentage NaCl between (for example 10 or 20).
The crystallization of top step (f) can followingly be carried out: with the solution left standstill in the alcoholic solvent, and/or, if use the temperature that raises in the post-processing step formerly, solution is cooled to for example envrionment temperature, any temperature of from 10 to 30 ℃ for example, for example from 17 to 23 ℃ (for example 20 ℃).In addition, precipitation solvent (for example dialkyl ether, for example diisopropyl ether) can be joined in the alcoholic solution, impel the crystallization of formula IX compound.
In another embodiment, can be with the compound of acid salt isolated in form formula IX.In this embodiment, acid salt be choose wantonly under the existence of suitable solvent system (organic solvent for example, isopropyl acetate for example, ethanol or its mixture), by formula I compound is formed with sour the contact.The specific acid additive salt that can mention comprises hydrobromate and L-tartrate.
Crystallized product can utilize technical point known to the skilled from, for example filter, with solvent wash and evaporating solvent, for example under those conditions described below for example.
If necessary, can the known technology of use technology personnel be further purified product, those technology for example described herein.
As mentioned above, the compound of formula X, XI and XII can mix with alkali in advance, then makes the reactant salt of they and formula I.Thisly be pre-mixed salt that following advantage: formula I is provided and the reaction between formula X, XI or the XII compound, can be simply by filtering beginning, directly change the mixture of alkali and formula X, XI or XII compound into, this mixture is the solution that method obtained that carries out according to first aspect of the present invention.The minimum numberization that this can make amount of solvents and carry out hydrogenation and the required container of coupling step.
Similarly, as described above, preferably between the compound of the salt of defined formula I above and formula XII, carry out coupling.Further, preferred alkali comprises alkali aqueous solution.
Therefore, according to a third aspect of the present invention, provide basically by the following mixture of forming:
(1) alkali aqueous solution; With
(2) compound of formula XII as hereinbefore defined.
About this respect of the present invention, preferred bases and formula XII compound are as mentioned above.Particularly, preferred bases is alkaline carbonate (a for example yellow soda ash), and the compound of formula XII is 4-(epoxy ethyl methoxyl group) benzonitrile, or 4-[(2S particularly)-the epoxy ethyl methoxyl group] benzonitrile.
Except as otherwise noted, when quoting molar equivalent and stoichiometric ratio herein, suppose and use every equimolar acid or alkali only to provide or accept a moles of hydrogen ionic bronsted lowry acids and bases bronsted lowry respectively for bronsted lowry acids and bases bronsted lowry.Consider to use to have the bronsted lowry acids and bases bronsted lowry that gives or accept hydrogen ion ability more than a mole, need the corresponding conversion of the molar equivalent of quoting and stoichiometric ratio.Therefore, for example,, compare during so with employing monoprotic acid, only need half molar equivalent if the acid of adopting is diproton acid.Similarly, use single alkali cpd (NaHCO for example with needs 3) compare, use two alkali cpds (Na for example 2CO 3) only need the employed alkali of half molal quantity.
The technician is appreciated that some compound of formula IX can prepare by some other compound of formula IX or by related compound on the structure.For example, the compound of formula IX (R wherein 1Some structure fragment of expression IXa) can be according to the respective compound of methods involving known in the art, through type IX (R wherein 1The different structure fragment of expression IXa) the preparation that is converted mutually (for example, utilizing the similar approach of method described in international patent application numbering WO 99/31100, WO 00/76997, WO 00/76998, WO 00/76999, WO 00/77000 and the WO 01/28992).
It will be understood by those skilled in the art that in aforesaid method perhaps the functional group of reagent maybe may need to protect by protecting group.
Under any circumstance, wish that the functional group that protects comprises hydroxyl and amino.The appropriate protection base of hydroxyl comprises trialkylsilkl and alkyl diaryl silyl (t-butyldimethylsilyl for example; t-butyldiphenylsilyl or trimethyl silyl), THP trtrahydropyranyl and alkyl-carbonyl (for example methyl carbonyl-and ethyl carbonyl).Amino appropriate protection base comprises amino protecting group mentioned above, benzyl for example, alkylsulfonyl (for example benzenesulfonyl or 4-oil of mirbane alkylsulfonyl), tertbutyloxycarbonyl, 9-fluorenyl-methoxycarbonyl or carbobenzoxy-(Cbz).
The protection of functional group and deprotection can carry out before or after any reactions steps as described above.
Protecting group can be removed according to technology well-known to those skilled in the art and technology described below.
The use of protecting group is described in " Protective Groups in Organic Chemistry " J.W.F.McOmie and edits, Plenum Press (1973) and " Protective Groups in OrganicSynthesis " third edition, T.W.Greene ﹠amp; P.G.M.Wutz is among the Wiley-Interscience (1999).
The salt that has following advantage: formula I according to the method for first aspect of the present invention prepares by certain method, and the reagent that this method is used than the method for WO 02/083690 lacks, and the solvent that uses than the method for WO2004/035592 lacks.In addition, present method has extra advantage: it can (promptly comprise water and C with the form of the operated subsequently IX compound of being more convenient for 3-5Solution form in the solvent systems of secondary alkyl alcohol) provides the salt of formula I.
Compare with the method that WO 02/083690 and WO 2004/035592 describes, have following advantage according to the method for second aspect of the present invention: the preparation productive rate is higher, and method comprises still less step, uses still less reagent and solvent.
Under any circumstance, compare with disclosed method in the prior art, the preparation productive rate that has the salt of following advantage: formula I or formula IX compound according to the inventive method is higher, purity is higher, step still less, the time is still less, mode more easily, form (for example more maneuverable form) (for example is easy to handle) the precursor preparation by more easily more easily, and the lower cost and/or the use of material and/or consumption are still less.
When using herein, term " relative volume " (rel.vol.) is meant the volume (milliliter) of the every gram reagent that uses.
When using herein, " basically " is meant at least and is preferably greater than 75%, for example greater than 95%, especially greater than 99% greater than 50%.
By the following example the present invention is described, but never is restrictive.
Synthesizing of intermediate
Following intermediate can commercially not bought, therefore by method preparation as described below.
Preparation example A
4-(2-bromine oxethyl)-3-fluoro benzonitrile
(i) 4-bromo-2-fluorophenol
The bromine (68.7 milliliters, 1.339 moles) that will be dissolved in the acetic acid (300 milliliters) dropwise joins in acetic acid (1300 milliliters) cooling solution of 2-fluorophenol (150 grams, 1.339 moles).The mixture that obtains at room temperature stirred spend the night, then use the aqueous solution of sodium bisulfite cancellation, and use dichloromethane extraction.With organic layer water and salt water washing, use dried over sodium sulfate then.Solvent evaporated under reduced pressure obtains 4-bromo-2-fluorophenol (210 gram) liquid.It is not further purified and is directly used in next step.
(ii) 4-bromo-2-fluoro-1-anisole
At 0 ℃, methyl iodide (182.1 milliliters, 1.319 moles) is joined 4-bromo-2-fluorophenol (210 grams, 1.099 moles; Referring to top step (i)) and K 2CO 3In the abundant stirred suspension of dry acetone (1.7 liters) of (303.92 grams, 2.19 moles).In nitrogen atmosphere, at 60 ℃, continue to stir two days, then reaction mixture is filtered, and the concentrating under reduced pressure solvent.4-bromo-2-fluoro-1-anisole (225 gram) liquid is provided, and it is not further purified and is directly used in next step.
(iii) 3-fluoro-4-HOMOVERATRONITRILE
At 120 ℃, with 4-bromo-2-fluoro-1-anisole (107 grams, 0.52 mole; Referring to top step (ii)), the mixture of CuCN (70.4 grams, 0.78 mole) stirs in dry DMF (150 milliliters) and spends the night.Reaction mixture is cooled to room temperature, dilute with water, and use ethyl acetate extraction.With organic layer water and salt water washing, use dried over sodium sulfate then.Solvent evaporated under reduced pressure is then used silica gel chromatography, uses 3% ethyl acetate/petroleum ether as elutriant, obtains 24.4 gram subtitle compounds solids.
(iv) 3-fluoro-4-hydroxy benzonitrile
At-78 ℃, with BBr 3(23 milliliters, 0.242 mole) join 3-fluoro-4-methoxyl group-benzonitrile (24.4 grams, 0.16 mole; In methylene dichloride referring to top step (iii)) (200 milliliters) solution.At room temperature continue to stir to spend the night.At-78 ℃, add another part BBr 3(23 milliliters, 0.242 mole), and continue further to stir 2 days in room temperature, in nitrogen atmosphere.With reaction mixture frozen water cancellation, and use dichloromethane extraction.With organic layer water and salt water washing, use dried over sodium sulfate then.Solvent evaporated under reduced pressure obtains 20 gram subtitle compounds solids.It is not further purified and is directly used in next step.
(v) 4-(2-bromine oxethyl)-3-fluoro benzonitrile
60 ℃, in nitrogen atmosphere, with 3-fluoro-4-hydroxy benzonitrile (20 the gram, 0.1459 mole; Referring to top step (iv)), anhydrous K 2CO 3(40.33 grams, 0.2918 mole) and dry DMF (150 milliliters) suspension of glycol dibromide (76.8 milliliters, 0.8754 mole) stirred 5 days.Reaction mixture is passed through Celite Filter, and solvent evaporated under reduced pressure.Use the silica gel chromatography resistates, use 2% ethyl acetate/petroleum ether, obtain 21.6 gram title compound solids as elutriant.
Preparation example B
2-(4-cyano group-2-fluorophenoxy) ethyltoluene-4-sulphonate
Scheme I
(i) 3-fluoro-4-(2-hydroxy ethoxy) benzonitrile
In potassium tert.-butoxide (19.35 gram), add ethylene glycol (160 milliliters).Then with mixture heating up to 50 ℃.At 50 ℃, add 3,4-two fluoro benzonitriles (20 gram), and its spent glycol (40 milliliters) washed.The solution that merges is heated to 80 ℃, under this temperature, kept two hours, then be cooled to 20 ℃ with one hour.Filter reaction mixture, and spent glycol (40 milliliters) washing.In filtrate, add entry (200 milliliters) and methylene dichloride (200 milliliters).Separate each layer, and, obtain subtitle compounds waxy white solid (26.1 grams, 100% productive rate) the organic layer vacuum concentration.
1H-NMR(CDCl 3，300MHz)δ7.48-7.34(m，2H，CH ar)，7.05(t，J＝8.3Hz，1H，CH ar，4.21(t，J＝4.5Hz，2H，CH 2)，4.08-3.98(m，2H，CH 2)。
If necessary, can use following method with 3-fluoro-4-(2-hydroxy ethoxy) benzonitrile recrystallization.
Adding toluene (20 milliliters) in 3-fluoro-4-(2-hydroxy ethoxy) benzonitrile (4.0 gram), and with this mixture heating up to 65 ℃.At 65 ℃, all substances are all dissolved.Mixture is cooled to room temperature (about 20 ℃).Between 45 and 40 ℃, observe crystallization.Reaction mixture further is cooled to 5 ℃.Filter reaction mixture, and wash with toluene (5 milliliters).At 35 ℃,, obtain subtitle compounds off-white color crystalline solid (3.38 grams of purifying with the solid vacuum-drying of humidity; 85% productive rate).
1H-NMR(CDCl 3，300MHz)δ7.46-7.34(m，2H，CH ar)，7.04(t，J＝8.3Hz，1H，CH arCF ar)，4.21(t，J＝4.5Hz，2H，C arOCH 2)，4.03(q，J＝5.1Hz，2H，CH 2OH)，2.09(t，J＝6.3Hz，1H，OH)。
(ii) 2-(4-cyano group-2-fluorophenoxy) ethyltoluene-4-sulphonate
To 3-fluoro-4-(2-hydroxy ethoxy) benzonitrile (47.6 grams; Referring to top step (i)) the middle methylene dichloride (380 milliliters) that adds.To wherein adding triethylamine (55 milliliters),, add the solution of the Tosyl chloride (50 gram) that is dissolved in the methylene dichloride (380 milliliters) then with about 60 minutes.Water (380 milliliters) is joined in the mixture that obtains, separate each layer.(organic) layer of vacuum concentration bottom obtains title compound white solid (87.9 grams; 99.8%).
If necessary, can use following any method, title compound is carried out recrystallization.
Method 1
In 2-(4-cyano group-2-fluorophenoxy) ethyltoluene-4-sulphonate (167.7 gram), add ethyl acetate (1.65 liters).Then this mixture heating up is extremely refluxed (about 78 ℃), this moment, all substances were all dissolved.Reaction mixture is cooled to room temperature (about 20 ℃).Between 70 ℃ and 75 ℃, observe crystallization.Reaction mixture is cooled to 5 ℃.Filtering mixt is with ethyl acetate (165 milliliters) washing.At 35 ℃,, obtain title compound white crystalline solid (103.3 grams of purifying with the solid vacuum-drying of humidity; 61.6%).
Method 2
In 2-(4-cyano group-2-fluorophenoxy) ethyltoluene-4-sulphonate (10 gram), add toluene (75 milliliters) and acetonitrile (5 milliliters).With mixture heating up to 80 ℃.At 80 ℃, all substances are all dissolved.Reaction mixture is cooled to room temperature (about 20 ℃).Between 55 ℃ and 50 ℃, observe crystallization.Reaction mixture further is cooled to 5 ℃.Filtering mixt is with toluene (10 milliliters) washing solid.At 35 ℃,, obtain title compound off-white color crystalline solid (9 grams of purifying with about 18 hours of the solid vacuum-drying of humidity; 90% productive rate).
Method 3
In 2-(4-cyano group-2-fluorophenoxy) ethyltoluene-4-sulphonate (10 gram), add toluene (75 milliliters).With this mixture heating up to 95 ℃.At 95 ℃, all substances are all dissolved.Reaction mixture is cooled to room temperature (about 20 ℃).Between 65 ℃ and 60 ℃, observe crystallization.Reaction mixture further is cooled to 5 ℃.Filtering mixt is with toluene (10 milliliters) washing solid.At 35 ℃,, obtain title compound off-white color crystalline solid (9.4 grams of purifying with about 17 hours of the solid vacuum-drying of humidity; 94% productive rate).
Scheme II
At 20 ℃, in 3-fluoro-4-hydroxy benzonitrile (0.2 kilogram), add acetonitrile (0.85 liter).To wherein adding salt of wormwood (404 gram); It is washed with acetonitrile (0.18 liter).Then reaction is heated to 80 ℃ ± 5 ℃, approximately per minute is 1 ℃.When reaction mixture during, with adding 2-monobromethane-1-alcohol (0.31 liter) in about 20 minutes at 80 ℃ ± 5 ℃.It is washed with acetonitrile (0.18 liter).With temperature regulation to 80 ℃ ± 5 ℃, and under this temperature, kept six hours.Reaction is heated to 30 ℃ then, approximately per minute is 1 ℃.For simplicity, will be reflected at 30 ℃ kept about 12 hours.Then toluene (1.6 liters) and water (1.34 liters) are joined in the reaction mixture.With reaction mixture reheat to 30 ℃.Separate each layer, and remove down (moisture) layer (about 1.2 liters).(organic) layer is removed the solvent (under less than 55 ℃ of conditions, about 1.2 liters) of about six volumes in the underpressure distillation.Reaction mixture is cooled to 20 ℃ then, analyzes water-content (generally＜0.1%w/w).To wherein adding triethylamine (245 milliliters), and reaction mixture is cooled to-10 ℃.Solution to wherein adding trimethylamine hydrochloride (28 gram), then add the Tosyl chloride (292 gram) that is dissolved in the toluene (1.2 liters) maintains the temperature at-10 ℃ ± 10 ℃ simultaneously.When adding is finished, reaction mixture is warmed to 20 ℃.To wherein adding entry (1.2 liters), and reaction mixture is heated to 75 ℃.At 75 ℃, separate each layer, remove down (moisture) layer.In the organic layer that keeps, add 1M hydrochloric acid (1.2 liters), and reaction mixture is heated to 80 ℃.Separate each layer, remove down (moisture) layer.Be cooled to 20 ℃ with going up (organic) layer about two hours.For simplicity, reaction mixture was kept about 12 hours at 20 ℃.With about 30 minutes reaction mixture is cooled to 5 ℃ then.Reaction mixture was kept about one hour at 5 ℃.Filtering mixt washs the crude product solid then with toluene (200 milliliters, 5 ℃).At 35 ℃,, obtain title compound white crystalline solid (373 grams, 76% productive rate) with the about twenty four hours of solid vacuum-drying of humidity.
1H-NMR(CDCl 3，300MHz)δ7.80(d，J＝8.4Hz，2H，CH ar)，7.41-7.32(m，4H，CH ars)，6.94(d，J＝8.2Hz，1H，CH ar)，4.44-4.38(m，2H，CH 2)，4.34-4.28(m，2H，CH 2)，2.45(s，3H，ArCH 3)。
Preparation example C
[3-(7-benzyl-9-oxa--3,7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-yl) propyl group] carboxylamine uncle Butyl ester, the 4-closilate
Methyl iso-butyl ketone (MIBK) (MIBK) (800 milliliters) solution and 2.5M sodium hydroxide (310 milliliters) solution that in 3-propantheline bromide hydrobromide (139.32 grams, 636.40 mmoles), add two-tertiary butyl, two carbonic ethers (112.46 grams, 510.13 mmoles).The mixture that obtains was at room temperature stirred 1 hour.By TLC (9: 1 isohexanes: ethyl acetate 4: 1, potassium permanganate dyeing) monitoring reaction.Add entry (345 milliliters), and stirred the mixture 10 minutes.Separate each phase, remove following (moisture) phase.In the organic phase that keeps, add 3-benzyl-9-oxa--3,7-diazabicyclo [3.3.1] nonane dihydrochloride (148.43 grams, 509.68 mmoles; Referring to WO 02/083690) and 2.5M sodium hydroxide (660 milliliters).Mixture was heated 7 hours at 65 ℃.At 65 ℃, separate each phase, remove following (moisture) phase.With organic phase reheat to 65 ℃, extract with 10%w/w aqueous citric acid solution (562 milliliters).Separate each phase, the phase of (organic) above removing.Add methyl iso-butyl ketone (MIBK) (800 milliliters) and 5M sodium hydroxide (230 milliliters) (containing about 10%w/v sodium-chlor (22.84 gram)) to the aqueous phase that obtains.The mixture that obtains was at room temperature stirred 15 minutes.Separate each phase, the phase of (moisture) below removing.Remove desolvate (300 milliliters) and come the azeotropic drying organic phase by decompression (keeping temperature to be lower than 70 ℃) distillation.When being still heat, solution, uses MIBK (115 milliliters) debris by filtering clarified mixture.With temperature regulation to 60 ℃, and with the MIBK solution (225 milliliters) that added purifying (referring to J.Am.Pharm.Assoc.239-241 (1949)) 4-chlorobenzenesulfonic acid (99.24 grams, 515.20 mmoles) in 90 minutes.Then reaction mixture is cooled to room temperature, causes product crystallization from solution.Mixture is cooled to 5 ℃, filters and collect product, with MIBK (225 milliliters) washing leaching cake.Product is dry on strainer as far as possible, and vacuum drying (50 ℃, 24 hours) obtains title compound white solid (257.44 grams, 453.13 mmoles, 89%) then.
1H NMR (300MHz, DMSO-d 6) δ 7.61 (d, J=8.7Hz, 2H), 7.46-7.35 (m, 7H), 7.10 (t, J=5.7Hz, 1H), 4.15 (s, 2H), 3.70 (s, 2H), 3.40 (d, J=12.1Hz, 3H), 3.07 (d, J=11.9Hz, 4H), 2.97 (q, J=6.3Hz, 2H), 2.84 (t, J=7.1Hz, 2H), 2.76 (d, J=11.9Hz, 2H), 1.70 (quintet, J=6.7Hz, 2H), 1.45 (s, 9H).
Preparation example D
3-(4-cyano-benzene oxygen propyl group) 4-toluene sulfonic acide ester
Scheme I
(i) 4-(3-hydroxyl propoxy-) benzonitrile
In flask, add the 4-hydroxy benzonitrile (50 grams, 0.41 mole, 1eq) and salt of wormwood (0.51 mole, 1.25eq).In this mixture, add 4-methyl-2--pentanone (400 milliliters).Begin to stir, and disposable adding 3-bromo-1-propyl alcohol (61.50 grams, 0.4 mole, 1.05eq).Reaction mixture is heated between 85 and 90 ℃, kept 5 hours.Add entry (250 milliliters) then, and with the mixture heating up to 30 that obtains ℃, till all solid dissolvings.From organic layer, separate water layer.With 4-methyl-2 pentanone (400 milliliters) dilution organic layer, the solution of subtitle compounds is provided, it is not further purified and is directly used in next step.
GC:95% purity, LC:96.50%
GC-MS：m/z＝177。
1H NMR (300MHz, CDCl 3) δ 1.50 (t, J=5.7Hz, 1H), 2.07 (quintet, J=6.0Hz, 2H), 3.87 (q, J=5.7Hz, 2H), 4.17 (t, J=6.0Hz, 2H), 6.96 (dd, J=6.9,2.1Hz, 2H), 7.59 (dd, J=6.9,2.1Hz, 2H).
(ii) 3-(4-cyano-benzene oxygen propyl group) 4-toluene sulfonic acide ester
The solution decompression that top step (i) is produced distills (50 ℃ of distillation temperatures, 100 millibars of pressure).Distill out about 500 milliliters of solvents.The about 0.002%w/w of the water-content of resistates.With 4-methyl-2 pentanone (400 milliliters) dilution resistates, and the adding triethylamine (53.70 grams, 0.53 mole, 1.25eq).Reaction mixture is cooled to-15 ℃, and the adding trimethylamine hydrochloride (8.16 grams, 0.083 mole, 0.2eq).(85.80 grams, 0.445 mole, 4-methyl-2 pentanone 1eq) (400 milliliters) solution keeps temperature to be lower than-10 ℃ simultaneously to add Tosyl chloride in this stirred solution.Reaction mixture is being lower than under-10 ℃ of conditions stirring 3 hours, then be warmed to room temperature at leisure, under this temperature, further continuing to stir 18 hours.Water (300 milliliters) is joined in the reaction mixture, and with the slurries heating (about 85 ℃) that obtain, till all solid dissolvings.From organic layer, separate water layer.In organic layer, add hydrochloric acid (200 milliliters, 1M).Then with the mixture heating up (about 85 ℃) that obtains, till all solids become solution.From organic layer, separate water layer.Organic layer is transferred to room temperature, and cooling (5 ℃) is 2 hours then.The filtering separation precipitated solid is with 4-methyl-2 pentanone (100 milliliters) washing, then drying under reduced pressure in 50 ℃ of baking ovens.Obtain title compound colorless solid (114.25 grams, 82%).
1H-NMR(300MHz，CDCl 3，)δ2.11-2.19(2H，m)，3.99-4.04(2H，t)，4.22-4.26(2H，t)，6.81-6.84(2H，m)，7.25-7.26(2H，m)，7.54-7.58(2H，m)，7.74-7.77(2H，m)。
LC?98.7％。
(M+H+ acetonitrile) +=373.
Scheme II
(i) 4-(3-hydroxyl propoxy-) benzonitrile
In flask, add the 4-hydroxy benzonitrile (50 grams, 0.41 mole, 1eq) and toluene (400 milliliters).With the mixture heating up to 65 that obtains ℃ ± 5 ℃.In this stirred reaction mixture, add 3-bromo-1-propyl alcohol (72.90 grams, 0.51 mole, 1.25eq), then in 20 minutes, add sodium hydroxide (210 milliliters, 2.5M, 0.52 mole, 1.25eq).Reaction is heated to 65 to 70 ℃, kept 17 hours.At 60 to 65 ℃, from organic layer, separate water layer.Then organic layer need not be further purified and be directly used in next step.
LC purity 95.3%.
1H NMR (300MHz, CDCl 3) δ 1.50 (t, J=5.7Hz, 1H), 2.07 (quintet, J=6.0Hz, 2H), 3.87 (q, J=5.7Hz, 2H), 4.17 (t, J=6.0Hz, 2H), 6.96 (dd, J=6.9,2.1Hz, 2H), 7.59 (dd, J=6.9,2.1Hz, 2H).
(ii) 3-(4-cyano-benzene oxygen propyl group) 4-toluene sulfonic acide ester
Toluene (400 milliliters) is joined in the solution of abovementioned steps generation.Underpressure distillation goes out about 330 milliliters of solvents (at 50 ℃).In resistates, add toluene (200 milliliters) and triethylamine (53.70 the gram, 0.53 mole, 1.25eq).Reaction mixture is cooled to-15 ℃, and the adding trimethylamine hydrochloride (8.16 grams, 0.083 mole, 0.2eq).(85.80 grams, 0.445 mole, toluene 1eq) (300 milliliters) solution keeps temperature to be lower than-10 ℃ simultaneously to add Tosyl chloride in this stirred solution.The Tosyl chloride of remnants is flushed in the reaction mixture with toluene (100 milliliters).Be lower than under-10 ℃ of conditions stirred reaction mixture 3 hours.Reaction mixture is warming up to room temperature at leisure, then stirred 18 hours.Water (300 milliliters) is joined in the reaction mixture, and with the slurries heating (about 85 ℃) that obtain, till all solids become solution.From organic layer, separate water layer.In organic layer, add hydrochloric acid (200 milliliters, 1M).Organic layer is cooled to room temperature, is cooled to about 5 ℃ then, under this temperature, it was stirred 2 hours.The filtering separation precipitated solid is used toluene (100 milliliters) washing then.With product drying under reduced pressure in baking oven (at 50 ℃), obtain title compound colorless solid (94.20 grams, 67%).
LC purity 99.1%
(M+H+ acetonitrile) +=373.
1H NMR (300MHz, CDCl 3) δ 2.15 (quintet, J=5.9Hz, 2H), 2.43 (s, 3H), 4.01 (t, J=5.9Hz, 2H), 4.24 (t, J=5.9Hz, 2H), 6.83 (dd, J=6.9,1.9Hz, 2H), 7.26 (t, J=3.9Hz, 6H), 7.56 (t, J=16.2Hz, 2H), 7.75 (d, J=8.2Hz, 2H).
Scheme III
(i) 4-(3-hydroxyl propoxy-) benzonitrile
In flask, add the 4-hydroxy benzonitrile (10 grams, 82.7 mmoles, 1eq) and salt of wormwood (13.60 restrain, 98.7 mmoles, 1.25eq).In this mixture, add acetonitrile (80 milliliters), then, under agitation condition, adding 3-bromo-1-propyl alcohol (12.25 grams, 86.40 mmoles, 1.05eq).With reaction mixture refluxed (84 ℃) heating 5 hours, then be cooled to room temperature.Add toluene (80 milliliters) and water (50 milliliters), and with the mixture heating up (30 ℃ of ≈) that obtains, till all solids dissolving.From organic layer, separate water layer.Keep organic layer.
1H-NMR (300MHz, CDCl 3) δ 1.50 (t, J=5.7Hz, 1H), 2.07 (quintet, J=6.0Hz, 2H), 3.87 (q, J=5.7Hz, 2H), 4.17 (t, J=6.0Hz, 2H), 6.96 (dd, J=6.9,2.1Hz, 2H), 7.59 (dd, J=6.9,2.1Hz, 2H).
(ii) 3-(4-cyano-benzene oxygen propyl group) 4-toluene sulfonic acide ester
With the solution distillation that top step (i) produces, remove 40 milliliters of solvents.Make the mixture cool to room temperature then, then add triethylamine (10.09 the gram, 98.7 mmoles, 1.25eq).Reaction mixture is cooled to-15 ℃, and the adding trimethylamine hydrochloride (1.57 grams, 16.45 mmoles, 0.2eq).(toluene 1.05eq) (60 milliliters) solution keeps temperature to be lower than-10 ℃ simultaneously for 16.47 grams, 86.38 mmoles to add Tosyl chloride in this stirred reaction mixture.Be lower than under-10 ℃ of conditions, stirred reaction mixture 3 hours then is warming up to room temperature.Add entry (60 milliliters), and the slurries that obtain are heated to about 60 ℃, till all solid dissolvings.From organic layer, separate water layer, and with hydrochloric acid (60 milliliters 0.5M) join in the organic layer.With the mixture heating up that obtains to about 62 ℃, till all solids become solution.From water layer, separate organic layer, be cooled to room temperature, stirred 2 hours down at about 5 ℃ then.The filtering separation precipitated solid is used toluene (20 milliliters) washing then.With product drying under reduced pressure in baking oven (at 40 ℃), obtain title compound colorless solid (19.92 grams, 73%).
1H-NMR(300MHz，CDCl 3，)δ2.11-2.19(2H，m)，3.99-4.04(2H，t)，4.22-4.26(2H，t)，6.81-6.84(2H，m)，7.25-7.26(2H，m)，7.54-7.58(2H，m)，7.74-7.77(2H，m)。
LC?99.6％。
(M+H+ acetonitrile) +=373.
Embodiment
Embodiment 1
2-{7-[(2S)-3-(4-cyano-benzene oxygen)-2-hydroxypropyl]-9-oxa--3,7-diaza-two ring [3.3.1] ninth of the ten Heavenly Stems-the 3-yl ethyl carbamic acid tertiary butyl ester
Scheme 1
(a) [2-(9-oxa--3,7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-yl) ethyl] carboxylamine tertiary butyl Ester, 2,4,6-tri-methyl p-toluenesulfonate salt
Will [2-(7-benzyl-9-oxa--3,7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-yl) ethyl] carboxylamine tertiary butyl ester 2,4,6-tri-methyl p-toluenesulfonate salt (150 grams; Referring to, for example, WO 2004/035592), Virahol (IPA; 450 milliliters) and water (150 milliliters) in the metal hydride container, mix.Add solid 5%Pd/C catalyzer (4.5 restrain, and 61% water is wet, Johnson Matthey type 440).Then under the 2.5bar hydrogen pressure with mixture hydrogenation, be heated to 55 ℃ simultaneously.Gas absorption is measured and is shown, reaction is finished after 1 hour.Be cooled to after 39 ℃, remove by filter catalyzer by glass fiber filter paper.On strainer, wash catalyzer, and the filtrate and the washing lotion that merge are used in next step with IPA (150 milliliters).
(b) 2-{7-[(2S)-3-(4-cyano-benzene oxygen)-2-hydroxypropyl]-9-oxa--3,7-diaza-two The ring [3.3.1] ninth of the ten Heavenly Stems-the 3-yl ethyl carbamic acid tertiary butyl ester
Aqueous sodium carbonate (1M, 133 milliliters) is joined [2-(9-oxa--3,7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-yl) ethyl] carboxylamine tertiary butyl ester, 2,4, in the solution of 6-tri-methyl p-toluenesulfonate salt (referring to top step (a)).Add 4-[(2S)-the epoxy ethyl methoxyl group] benzonitrile (44.4 grams; Referring to, for example WO 01/28992) IPA (75 milliliters) and toluene (75 milliliters) solution.Reaction is heated to 73 ℃, kept 4 hours, then with it in stirred overnight at room temperature.Under less than 84 ℃ of conditions, distillation removes desolvate (440 milliliters).Add toluene (1 liter), and with solvent distillation (52 milliliters in water, 441 milliliters of organic solvents).Further add part toluene (500 milliliters), solvent distillation (82 milliliters in water, 437 milliliters of organic solvents) once more.Then mixture is cooled to envrionment temperature.Add aqueous sodium hydroxide solution (1M, 450 milliliters), and mixture was stirred 5 minutes, separate each phase then.Remove water, with aqueous citric acid solution (10%w/v, 450 milliliters) washing toluene phase.Remove the toluene phase.With 4-methyl-2-amylalcohol (MIBC; 600 milliliters) and aqueous sodium hydroxide solution (5M, 450 milliliters) join citric acid mutually in.Stir after 5 minutes, separate each phase, remove the aqueous solution.MIBC is used sodium chloride aqueous solution (20%w/v, 150 milliliters) washing mutually.The mixture of concentrating under reduced pressure MIBC and sodium chloride aqueous solution under less than 50 ℃ of conditions, (collecting water (20 milliliters) and MIBC (55 milliliters)).MIBC solution is cooled to 33 ℃, then its stirring is spent the night.Solution is filled in the clean container.Under less than 70 ℃ of conditions, underpressure distillation solvent (285 milliliters).Add diisopropyl ether (IPE; 900 milliliters), adding speed should keep temperature to be higher than 55 ℃.Solution is cooled to 23 ℃ then.After 90 minutes, the beginning crystallization stirred the mixture 15 minutes, then was cooled to 5 ℃.Filter and collect product.On strainer,, blot with IPE (300 milliliters) flushing solid.55 ℃ of further vacuum-dryings, obtain title compound white solid (92.5 grams, 78%, two step).
Scheme 2
(a) [2-(9-oxa--3,7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-yl) ethyl] carboxylamine tertiary butyl Ester, 2,4,6-tri-methyl p-toluenesulfonate salt
Will [2-(7-benzyl-9-oxa--3,7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-yl) ethyl] carboxylamine tertiary butyl ester 2,4,6-tri-methyl p-toluenesulfonate salt (150 grams; Referring to, for example, WO 2004/035592), Virahol (IPA; 225 milliliters) and water (75 milliliters) in the metal hydride container, mix.Add solid 5%Pd/C catalyzer (4.7 restrain, and 61% water is wet, Johnson Matthey type 440).Hydrogen is introduced in the container, begun to stir.Under the 2.5bar hydrogen pressure,, be heated to 55 ℃ (temperature upper punches to 73 ℃) simultaneously with mixture hydrogenation.Gas absorption is measured and is shown, reaction is finished after 1 hour.Be cooled to after 47 ℃, remove by filter catalyzer by glass fiber filter paper.On strainer, wash catalyzer, and the filtrate and the washing lotion that merge are used in next step with IPA (75 milliliters).
(b) 2-{7-[(2S)-3-(4-cyano-benzene oxygen)-2-hydroxypropyl]-9-oxa--3,7-diaza-two The ring [3.3.1] ninth of the ten Heavenly Stems-the 3-yl ethyl carbamic acid tertiary butyl ester
Will [2-(9-oxa--3,7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-yl) ethyl] carboxylamine tertiary butyl ester, 2,4,6-tri-methyl p-toluenesulfonate salt (referring to top step (a)) is heated to 55 ℃.Add aqueous sodium carbonate (1M, 133 milliliters), then add 4-[(2S)-the epoxy ethyl methoxyl group] benzonitrile (44.4 grams; Referring to, for example WO 01/28992) IPA (75 milliliters) and toluene (75 milliliters) heat (40 ℃) solution.Solution is gone in the reaction flask with IPA (37 milliliters) and toluene (37 milliliters) flushing.Reaction is heated to 78 ℃, kept 4 hours, then with it in stirred overnight at room temperature.Add toluene (1050 milliliters), solvent distillation (600 milliliters).Mixture is cooled to 26 ℃ then.Add aqueous sodium hydroxide solution (1M, 450 milliliters).Mixture was stirred 5 minutes, separate each phase then.Remove water, with aqueous citric acid solution (10%w/v, 450 milliliters) washing toluene phase.Remove the toluene phase.With 4-methyl-2-amylalcohol (MIBC; 600 milliliters) and aqueous sodium hydroxide solution (5M, 450 milliliters) join citric acid mutually in.Stir after 5 minutes, separate each phase, remove water.MIBC is used sodium chloride aqueous solution (20%w/v, 150 milliliters) washing mutually, separate each phase.Then the MIBC solution stirring is spent the night (stirred overnight is unnecessary, but for simplicity, carries out in this embodiment).Concentrating under reduced pressure MIBC phase (collecting 78 milliliters of solvents).Solution is filled in the clean container, with MIBC (150 milliliters) flushing.Under less than 70 ℃ of conditions, underpressure distillation solvent (437 milliliters).Add diisopropyl ether (IPE at 55 ℃; 900 milliliters), and reduce the temperature to 40 ℃.With solution reheat to 58 ℃, naturally cool to envrionment temperature (at 28 ℃, precipitation forms) then.Mixture stirred at ambient temperature spend the night.Mixture is cooled to 5 ℃, solid collected by filtration.With IPE (300 milliliters) slow rinse filter cake, suction filtration drying on strainer.70 ℃ of further vacuum-dryings, obtain title compound white solid (97.3 grams, 82%, two step).
Scheme 3
(a) [2-(9-oxa--3,7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-yl) ethyl] carboxylamine tertiary butyl Ester, 2,4,6-tri-methyl p-toluenesulfonate salt
Will [2-(7-benzyl-9-oxa--3,7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-yl) ethyl] carboxylamine tertiary butyl ester 2,4,6-tri-methyl p-toluenesulfonate salt (100 gram materials, 3.5%w/w water; Referring to, for example, WO 2004/035592) join in the metal hydride container.Add the Virahol (IPA that is pre-mixed; 150 milliliters) and water (50 milliliters).Add solid 5%Pd/C catalyzer (4.0 grams, 61% water-wet, Johnson Matthey type 440).Hydrogen is introduced in the container, begun to stir.Under the 3.5bar hydrogen pressure,, be heated to 55 ℃ (temperature upper punches to 68 ℃) simultaneously with mixture hydrogenation.Gas absorption is measured and is shown, reaction is finished after 3.5 hours.In the following proper timing of pointing out in detail, direct filtration is in next reaction vessel with reactant.With IPA (50 milliliters) washing catalyst, and, washing lotion is directly joined in the next reaction vessel in the following proper timing of pointing out in detail.
(b) 2-{7-[(2S)-3-(4-cyano-benzene oxygen)-2-hydroxypropyl]-9-oxa--3,7-diaza-two The ring [3.3.1] ninth of the ten Heavenly Stems-the 3-yl ethyl carbamic acid tertiary butyl ester
With the 4-[(2S that packs in the clean container)-the epoxy ethyl methoxyl group] benzonitrile (30.1 grams; Referring to, for example WO 01/28992), the aqueous sodium carbonate of then packing into (0.3M, 300 milliliters).Add [2-(9-oxa--3,7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-yl) ethyl] carboxylamine tertiary butyl ester, 2,4,6-tri-methyl p-toluenesulfonate salt (referring to top step (a)) solution then adds catalyzer washing lotion (referring to top step (a)).With mixture backflow (78 ℃) heating 4 hours, place 4 days (this time of repose is unnecessary, but for simplicity, leaves standstill in this embodiment) then at ambient temperature.Underpressure distillation removes desolvate (236 milliliters) (need distill out about 2.5 volume of solvent, to guarantee to remove IPA).Add toluene (400 milliliters) and aqueous sodium hydroxide solution (3M, 100 milliliters), and stirred the mixture 5 minutes.Separate each phase at 27 ℃, remove following water.With aqueous citric acid solution (10%W/V, 300 milliliters) join remaining toluene mutually in.Stir after 5 minutes, separate each phase, remove top toluene phase.With 4-methyl-2-amylalcohol (MIBC; 600 milliliters) and aqueous sodium hydroxide solution (5M, 450 milliliters) (containing sodium-chlor (10%w/v)) join citric acid mutually in.After 5 minutes, separate each phase 30 ℃ of stirrings, remove water.MIBC is used sodium chloride aqueous solution (20%w/v, 100 milliliters) washing mutually, after stirring 5 minutes, separate each phase.Then MIBC solution is placed and is spent the night (spending the night, to leave standstill be unnecessary, but for simplicity, carry out in this embodiment).Vacuum concentration MIBC phase under less than the temperature of 44 ℃ (top temperature that can reach in this part process is 70 ℃); Collect solvent (35 milliliters of 18 milliliters in water: MIBC).Solution is filled in the clean container, with MIBC (50 milliliters) flushing.Under less than 70 ℃ of conditions, vacuum distilling solvent (240 milliliters).Add diisopropyl ether (IPE; 600 milliliters), and with solution reheat to 64 ℃.Stirred solution under 250rpm, and naturally cooling.After stirring 2 hours, temperature drops to 28 ℃, begins to occur the product precipitation.After further stirring 90 minutes, temperature drops to 21 ℃.In 20 minutes, mixture is cooled to 5 ℃, under this temperature, kept 90 minutes then.Filter and collect product.With (200 milliliters of IPE; The IPE temperature is 20 ℃) the slow rinse filter cake, suction filtration drying on strainer.Spend the night at 35 ℃ of vacuum-drying products, obtain title compound white solid (65.2 grams, 85%, two step).
Scheme 4
(a) [2-(9-oxa--3,7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-yl) ethyl] carboxylamine tertiary butyl Ester, 2,4,6-tri-methyl p-toluenesulfonate salt
Will [2-(7-benzyl-9-oxa--3,7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-yl)-ethyl] carboxylamine tertiary butyl ester 2,4,6-tri-methyl p-toluenesulfonate salt (92.60 kilograms of materials, 17.51%w/w water; Referring to, for example, WO 2004/035592) and solid 5%Pd/C catalyzer (3.70 kilograms, 61% water-wet, Johnson Matthey type 440) join in the metal hydride container.Add the Virahol (IPA that is pre-mixed; 109.30 kilogram) and water (46.2 kilograms).With container with hydrogen purge to 0.5bar, to discharge nitrogen, then hydrogen is incorporated in the container, reach 3.0bar, begin to stir, begin to be heated to 55 ℃ (top temperature that reaches is 55.3 ℃) simultaneously.Reaction mixture was kept in atmosphere of hydrogen 1 hour 45 minutes, and then gas absorption stops, and shows to react to finish.Reaction mixture is cooled to 20 ℃ then, it is left standstill 21 hours 35 minutes (time of repose is unnecessary, but leaves standstill for simplicity).Reaction mixture is filled in the following next reaction vessel of pointing out,, and joins in the following next reaction vessel of pointing out with IPA (35.9 kilograms) washing catalyst filter cake.
(b) 2-{7-[(2S)-3-(4-cyano-benzene oxygen)-2-hydroxypropyl]-9-oxa--3,7-diaza-two The ring [3.3.1] ninth of the ten Heavenly Stems-the 3-yl ethyl carbamic acid tertiary butyl ester
With the 4-[(2S that packs in the clean container)-the epoxy ethyl methoxyl group] (22.50 kilograms of benzonitriles; Referring to, for example WO 01/28992), softening water (184.7 kilograms) and sodium carbonate solution (1M, 91.2 kilograms).Add [2-(9-oxa--3,7-diazabicyclo-[3.3.1] ninth of the ten Heavenly Stems-3-yl) ethyl] carboxylamine tertiary butyl ester, 2,4,6-trimethylbenzene-sulfonate (referring to top step (a)) also adds catalyzer washing lotion (referring to top step (a)).With 35 minutes with mixture heating up to 78 ℃, under this temperature, kept 4 hours, be cooled to 25.1 ℃ then, at room temperature place 84 hours 42 minutes (in this embodiment, time of repose is unnecessary, leaves standstill for simplicity).Underpressure distillation removes desolvate (215.3 kilograms).Add toluene (321.0 kilograms), and with the temperature regulation to 25.5 of reaction mixture ℃.Sodium hydroxide solution (3M, 101.7 kilograms) is joined in the reaction vessel, stirred 23 minutes.Stop to stir, with separating each phase in 30 minutes.Remove following water.Restart to stir top organic phase, add aqueous citric acid solution (10%w/w, 278.3 kilograms), stirred 23 minutes.Stop to stir, with separating each phase in 40 minutes.The water of bottom is forwarded in second container (VESSEL 2), remove top organic phase.Then that water is return in reaction vessel, begin to stir, add 4-methyl-2-amylalcohol (MIBC; 297.7 kilogram) and the sodium hydroxide solution (10M, 185.4 kilograms) and the sodium chloride solution (20%w/w, 111.1 kilograms) that are pre-mixed, stirred 15 minutes.Stop to stir then, with separating each phase in 30 minutes.Remove following water.Restart to stir, add sodium chloride solution (20%w/w, 111.1 kilograms), and the inclusion of reaction vessel was stirred 10 minutes.Stop to stir, with separating each phase in 18 minutes.Remove following water.Begin to stir, from the top organic phase that keeps, remove desolvate (42.3 kilograms) by underpressure distillation.Concentrated solution is changed in the clean container (VESSEL 3), and wash reaction vessel with water, remove remaining salt pollution thing.Organic phase is heated to 47.3 ℃ then, heat filtering is in clean reaction vessel.MIBC (37.3 kilograms) is joined among the VESSEL 3, be filled in the reaction vessel then, and merge with most solutions.Remove by underpressure distillation then and desolvate (240.3 kilograms), keep the temperature of mixture to be lower than 70 ℃, then, add diisopropyl ether (313.9 kilograms) temperature regulation to 53.1 ℃.With temperature regulation to 51.6 ℃, be cooled to 20 ℃ with 110 minutes then, it is left standstill 14 hours 49 minutes (this time of repose is unnecessary, but leaves standstill for simplicity).With 30 minutes slurries are cooled to 5 ℃ then, kept 30 minutes at 5 ℃.Filtering mixt adds cold (5 ℃) diisopropyl ether (134.5 kilograms) and carries out displacement washing then, with nitrogen purging filter cake 135 minutes (this is unnecessary, but just carries out for simplicity).Drying under reduced pressure solid on strainer 30 ℃ of heating 87 hours, obtains title compound white solid (49.05 kilograms, 80.7%) simultaneously then.
Scheme 5
(a) [2-(9-oxa--3,7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-yl)-ethyl 1-carboxylamine uncle fourth The base ester, 2,4,6-tri-methyl p-toluenesulfonate salt
Will [2-(7-benzyl-9-oxa--3,7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-yl) ethyl] carboxylamine tertiary butyl ester, 2,4,6-tri-methyl p-toluenesulfonate salt (150 gram materials, 3.33%w/w water; Referring to, for example, WO 2004/035592) join in the metal hydride container.Add the Virahol (IPA, 180 grams) and the water (75 gram) that are pre-mixed.Add solid 5%Pd/C catalyzer (6.0 grams, 61% water-wet, Johnson Matthey type 440).After the nitrogen purging, hydrogen is introduced in the container, begun to stir.Under the 3.5bar hydrogen pressure with mixture hydrogenation, simultaneously with being heated to 65 ℃ (temperature upper punches to 73 ℃) in 15 minutes.Gas absorption is measured and is shown, reaction is finished (comprising heat-up time) after 30 minutes.At 65 ℃ after further 30 minutes, reaction is cooled to 23 ℃, the proper timing of pointing out in detail below then, direct filtration is in next reaction vessel.With IPA (60 gram) washing catalyst, and the proper timing of pointing out in detail below, washing lotion is directly joined in the next reaction vessel.
(b) 2-{7-[(2S)-3-(4-cyano-benzene oxygen)-2-hydroxypropyl]-9-oxa--3,7-diaza-two The ring [3.3.1] ninth of the ten Heavenly Stems-the 3-yl ethyl carbamic acid tertiary butyl ester
With the 4-[(2S that packs in the clean container)-the epoxy ethyl methoxyl group] benzonitrile (44.3 grams (referring to, for example WO 01/28992), 0.98 molar equivalent, based on anhydrous [2-(and 7-benzyl-9-oxa--3,7-diazabicyclo [3.3.1]-ninth of the ten Heavenly Stems-the 3-yl) ethyl] the carboxylamine tertiary butyl ester, 2,4,6-tri-methyl p-toluenesulfonate salt), then add aqueous sodium carbonate (3%w/w, 480 grams).Add [2-(9-oxa--3,7-diaza-two ring [3.3.1] ninth of the ten Heavenly Stems-3-yl) ethyl] carboxylamine tertiary butyl ester, 2,4,6-trimethylammonium-benzene sulfonate (referring to top step (a)) solution then adds catalyst detergent liquid (referring to top step (a)).The mixture that obtains is extremely refluxed (78 ℃) at 30 minutes internal heating, under this temperature, kept 2 hours then.Reaction is cooled to 50 ℃.At≤50 ℃, underpressure distillation removes desolvate (353 gram).Add toluene (375 gram), and with temperature regulation to 28 ℃ ± 3 ℃.(all extractions subsequently operate under this temperature and carry out).Add aqueous sodium hydroxide solution (10%w/w, 180 grams), and mixture was stirred 5 minutes.Separate each phase, remove following water.With aqueous citric acid solution (10%w/w, 450 gram) join remaining toluene mutually in.Stir after 5 minutes, separate each phase, remove top toluene phase.With 4-methyl-2-amylalcohol (MIBC) (420 gram) and sodium hydroxide/sodium chloride aqueous solution (600 restrain for 15%w/w wrt NaOH, 7.5%w/w wrt NaCl) join citric acid mutually in.Stir after 5 minutes, separate each phase, remove water.MIBC is used sodium chloride aqueous solution (20%w/w, 75 grams) washing mutually, after stirring 5 minutes, separate each phase.At≤50 ℃, concentrating under reduced pressure MIBC phase (removing 84 gram solvents).Solution is filled in the clean container, with MIBC (60 gram) flushing.Under less than 70 ℃ of conditions, vacuum distilling goes out solvent (239 gram).Add isopropyl ether (IPE) (653 gram), and with more than the solution reheat to 55 ℃.Stirred solution, cool overnight.Second day, mixture is cooled to 5 ℃ from envrionment temperature with 15 minutes.After stirring 10 minutes, filter and collect product.With IPE (225 grams; The IPE temperature is 20 ℃) displacement washing filter cake, suction filtration drying then.At 55 ℃ of vacuum-drying products, obtain title compound white solid (100.2 grams, 87%, two step).
Scheme 6
(a) [2-(9-oxa--3,7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-yl) ethyl] carboxylamine tertiary butyl Ester, 2,4,6-tri-methyl p-toluenesulfonate salt
Will [2-(7-benzyl-9-oxa--3,7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-yl) ethyl] carboxylamine tertiary butyl ester, 2,4,6-tri-methyl p-toluenesulfonate salt (1.00 equivalents; 267.56 mmole; 150.30 the gram material, 3.21%w/w water; Referring to, for example, WO 2004/035592) join in the hydrogenation vessel.Add (3.00 moles of premixed Virahols; 229.30 milliliter; 180.00 gram) and (4.16 moles in water; 75.00 milliliter; 75.00 gram), then add 5% palladium/carbon (4.50 grams; About 57%w/w water; Engelhard 5398).Container is purged with nitrogen (3x) and hydrogen (2x), be charged to 2 crust hydrogen pressures then.Use solid stirring rake (being equipped with the arc impeller of handling again) to begin to stir (600rpm).Begin the reacting by heating mixture immediately, after 15 minutes, reaction reaches target temperature (65 ℃ ± 5 ℃).After 50 minutes total reaction times (comprising heat-up time), (4.846 liters exhaust no longer further to admit hydrogen; Theoretical volume usage quantity: 5.801 liters).Reaction is cooled to 25 ℃, and (1: 1 X: DCM is as elutriant, and wherein X is a chloroform: methyl alcohol: strong aqua, ratio are 80: 18: 2 by thin-layer chromatography; Silica gel applies, the potassium permanganate video picture) determine to react and finish.(if necessary, this cooling and sampling procedure can be omitted).Remove by filter catalyzer, directly enter in 500 milliliters of graduated cylinders.Use Virahol (783.75 mmoles then; 60.00 milliliter; 47.10 washing catalyst gram).
Overall solution volume in the graduated cylinder is 480 milliliters, with Virahol it is supplied 500 milliliters then.Solution weight in the graduated cylinder (containing title compound) is 461.5 grams.
Be used for preparing [2-(7-benzyl-9-oxa--3,7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-yl) ethyl] carboxylamine tertiary butyl ester of solution, 2,4, the weight of 6-tri-methyl p-toluenesulfonate salt in 500 ml solns is 150 grams, or 30%w/v.
Be used for preparing [2-(7-benzyl-9-oxa--3,7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-yl) ethyl] carboxylamine tertiary butyl ester of solution, 2,4, the weight of 6-tri-methyl p-toluenesulfonate salt in 461.5 gram solution are 150 grams, or 32.5%w/w.
(b) 2-{7-[(2S)-3-(4-cyano-benzene oxygen)-2-hydroxypropyl]-9-oxa--3,7-diaza-two The ring [3.3.1] ninth of the ten Heavenly Stems-the 3-yl ethyl carbamic acid tertiary butyl ester
With reaction flask 3%w/w aqueous sodium carbonate (95.10 mmoles of packing into; 326.40 milliliter; 336.00 gram).[2-(9-oxa--3,7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-yl)-the ethyl]-carboxylamine tertiary butyl ester that adds that upper section (a) produces, 2,4, (350 milliliters of 6-tri-methyl p-toluenesulfonate salt; Equal 105.2 grams [2-(7-benzyl-9-oxa--3,7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-yl) ethyl] carboxylamine tertiary butyl ester, 2,4,6-tri-methyl p-toluenesulfonate salt precursor; No water equivalent is 101.8 grams).With 5 fens clock times with mixture heating up to 40 ℃, under 200rpm, stir simultaneously add solid 4-[(2S)-the epoxy ethyl methoxyl group] benzonitrile (174.67 mmoles; 30.60 gram; Referring to, for example WO 01/28992), with 17 minutes reaction is heated to 75 ℃.To be reflected under this temperature and keep 2 hours.The weight of inclusions of flask is 678 grams.Apply vacuum, cause temperature drop to≤50 ℃, distillation removes desolvates.The flask inclusion weighs 422 grams (therefore mean and distill out 256 gram (2.44rel wt) solvents) now.With (2.85 moles of toluene; 301.88 milliliter; 263.00 gram) join (it is 40 ℃) in the flask inclusion.Add aqueous sodium hydroxide solution (10%w/w) (315.02 mmoles; 113.63 milliliter; 126.00 gram), then the mixture that obtains is cooled to 30 ℃.After 12 minutes, stop stirring, make each stable mutually (within 30 seconds, occurring stable).Separate each phase at 30 ℃, boundary material is stayed (removing) aqueous phase.(if necessary, can be on organic phase further with alkali aqueous solution for example the 10%w/w aqueous sodium hydroxide washes wash, to remove the trace sym-toluenesulfonic acid).With 10%w/w aqueous citric acid solution (163.96 mmoles; 302.83 milliliter; 315.00 the gram) join toluene mutually in.After 7 minutes, stop stirring, make each stable mutually (within 20 seconds, occurring stable).Separate each phase at 29 ℃, boundary material stay above (removing) (organic) mutually in.Add (2.88 moles of 4-methyl-2-amylalcohol (methyl isobutyl carbinol); 366.58 milliliter; 294.00 gram), then add sodium hydroxide (15%w/w) and sodium-chlor (7.5%w/w) (210.00 gram) aqueous solution.After 2 minutes, stop stirring, make each stable mutually (within 60 seconds, occurring stable).Separate each phase at 37 ℃, boundary material stay below (removing) (aqueous solution) mutually in.Add sodium chloride aqueous solution (20%w/w) (179.66 mmoles; 45.74 milliliter; 52.50 gram), stir.After 2 minutes, stop stirring, make each stable mutually (within 80 seconds, occurring stable).Separate each phase at 35 ℃, all boundary materials stay below (removing) (aqueous solution) mutually in.The weight of inclusions of flask is 395 grams.Vacuum distilling solution causes collecting 19 ml waters and 58 milliliters of MIBC.The flask inclusion weighs 317 grams (therefore mean to distill and remove 78 gram (0.75rel wt) solvents) now.Remaining solution is filled in the clean container, with MIBC (411.05 mmoles; 52.37 milliliter; 42.00 flushing gram).The weight of inclusions of new flask is 351 grams.Solution is placed spend the night (for simplicity).During this time, some crystallizations appear.With mixture heating up to 60 ℃, all materials have all dissolved.At≤70 ℃ of vacuum distilling solution, cause collecting 183 milliliters of liquid (the MIBC density based on 0.802, it is 1.4rel wt).With (3.24 moles of diisopropyl ether (diisopropyl ether); 457.00 milliliter; 331.32 gram) join in heat (70 ℃) the MIBC solution, cause the temperature of mixture to drop to 52 ℃.With solution reheat to 60 ℃, naturally cooling then.After 27 minutes, the flask inclusion reaches 45 ℃, adds crystal seed (56 milligrams).Mixture is cooled to 27 ℃ (these need 2 hours),, precipitation in a large number occurs through during this period of time.With 24 fens clock times mixture is cooled to 5 ℃, under this temperature, kept 1 hour then.Filter to collect product (this process need 45 seconds) then, with (1.54 moles of cold (5 ℃) DIPE; 217.24 milliliter; 157.50 washing gram) needed for 30 seconds.Filter cake is blotted as far as possible (10 minutes) on strainer.Then with the material of humidity (99 gram) vacuum-drying (at 55 ℃) to constant weight (needing 1.5 hours).Obtain title compound white solid (68.3 grams, 84%).
Embodiment 2
(2-{7-[2-(4-cyano group-2-fluorophenoxy) ethyl]-9-oxa--3,7-diazabicyclo-[3.3.1] The ninth of the ten Heavenly Stems-the 3-yl } ethyl) the carboxylamine tertiary butyl ester
Scheme 1
To [2-(7-benzyl-9-oxa--3,7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-yl) ethyl] carboxylamine tertiary butyl ester, 2,4,6-tri-methyl p-toluenesulfonate salt (100 grams; Referring to, for example, WO 2004/035592) middle Virahol (300 milliliters) and the water (100 milliliters) of adding.To wherein adding 5%w/w palladium/carbon (4 gram) (about 60% moistening mashed prod).Be heated to 65 ℃, and hydrogenation under 3.5bar.Reaction mixture was kept about 16 hours at 65 ℃, then be cooled to 20 ℃; The cumulative volume that absorbs hydrogen is 4 liters.Remove by filter catalyzer, with Virahol (50 milliliters) washing catalyst.With organic filtrate and the Virahol catalyzer washing lotion vacuum concentration that merges.Obtain white crystalline solid, it is received in the acetonitrile (1.28 liters).To wherein adding 4-(2-bromine oxethyl)-3-fluoro benzonitrile (43.5 grams; Referring to top preparation example A) and salt of wormwood (250 gram).Reaction is heated to backflow (about 80 ℃), under this temperature, kept four hours.Reaction mixture is cooled to about 20 ℃.Filter reaction mixture, and with acetonitrile (250 milliliters) washing leaching cake.With organic filtrate and the acetonitrile washing lotion vacuum concentration that merges, and resistates is received in the toluene (345 milliliters).Be heated 30 ℃ then, and keep this temperature, till extracting the aftertreatment end.Sodium hydroxide (12 gram) solution that in toluene solution, adds water-soluble (110 milliliters).Separate each phase, remove following (moisture) phase.Citric acid (30 gram) solution that in the organic layer that keeps, adds water-soluble (270 milliliters).Separate each layer, remove top (organic) layer.The sodium hydroxide (60 gram) and sodium-chlor (30 gram) solution that in the water layer that keeps, add ethyl acetate (330 milliliters) and water-soluble (310 milliliters).Separate each phase, remove following (moisture) phase.Sodium-chlor (10 gram) solution that in the organic layer that keeps, adds water-soluble (40 milliliters).Separate each phase, remove following (moisture) phase.With the dry ethyl acetate layer of sal epsom (10 gram), filter, and siccative is washed with ethyl acetate (220 milliliters).Merging is obtained organic filtrate and ethyl acetate washing lotion vacuum concentration, obtain the title compound light yellow oil, contain white crystals part (72.00 grams, 93% productive rate) within it.
If necessary, can use following method, title compound is carried out crystallization.
To (2-{7-[2-(4-cyano group-2-fluorophenoxy) ethyl]-9-oxa--3,7-diazabicyclo-[3.3.1] ninth of the ten Heavenly Stems-3-yl } ethyl) add Di Iso Propyl Ether (385 milliliters) and Virahol (77 milliliters) in the carboxylamine tertiary butyl ester (77 gram).With this mixture heating up to 65 ℃, under this temperature, kept 15 minutes, then be cooled to 5 ℃ with 90 minutes.Between 15 and 10 ℃, observe crystallization.Mixture was kept two hours at 5 ℃, and after-filtration washs with cold Di Iso Propyl Ether (80 milliliters, 5 ℃).At 35 ℃,, obtain crystallization title compound off-white color solid (54.5 grams with about 19 hours of the solid vacuum-drying of humidity; 71% productive rate).
1H-NMR(CDCl 3，300MHz)δ7.48-7.30(m)，7.15-6.96(m)，6.30-6.01(m)，4.58-4.23(m)，3.91-3.82(m)，3.27-3.08(m)，3.04-2.87(m)，2.85-2.59(m)，2.48-2.35(m)，1.40(s)。
Scheme 2
Example 1
To [2-(7-benzyl-9-oxa--3,7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-yl) ethyl] carboxylamine tertiary butyl ester, 2,4,6-tri-methyl p-toluenesulfonate salt (148 grams; Referring to, for example, WO 2004/035592) middle Virahol (450 milliliters) and the water (150 milliliters) of adding.To wherein adding 5%w/w palladium/carbon (7.5 grams, about 60% moistening mashed prod).With the mixture heating up to 65 that obtains ℃, and hydrogenation under 3.5 crust.Reaction mixture was kept about 14 hours at 65 ℃, then be cooled to 20 ℃; The cumulative volume that absorbs hydrogen is 5.9 liters.Remove by filter catalyzer, with Virahol (75 milliliters) washing catalyst.With organic filtrate and the Virahol catalyzer washing lotion vacuum concentration that merges, and the resistates (white crystalline solid) that obtains is received in the acetonitrile (1.9 liters).To wherein adding 2-(4-cyano group-2-fluorophenoxy) ethyltoluene-4-sulphonate (88.3 grams; Referring to top preparation example B) and salt of wormwood (91 gram).Reaction mixture is heated to backflow (about 80 ℃), under this temperature, kept eight hours, then be cooled to room temperature (about 20 ℃).Filter reaction mixture, and with acetonitrile (190 milliliters) washing leaching cake.With filtrate and the filter cake washing lotion vacuum concentration that merges, and the resistates that obtains is received in the toluene (850 milliliters).The sodium hydroxide of water-soluble to wherein adding (240 milliliters) (26.6 gram) solution.Separate each layer, remove following (moisture) layer.Citric acid (44.4 gram) solution that in the organic layer that keeps, adds water-soluble (400 milliliters).Separate each layer, remove top (organic layer).The sodium hydroxide (89 gram) and sodium-chlor (44.4 gram) solution that in the water layer that keeps, add ethyl acetate (1.25 liters) and water-soluble (460 milliliters).Separate each layer, remove following (moisture) layer.Sodium-chlor (15 gram) solution that in the organic layer that keeps, adds water-soluble (60 milliliters).Separate each layer, remove following (moisture) layer.With organic layer sal epsom (75 gram) drying that keeps.Remove by filter sal epsom, with ethyl acetate (410 milliliters) washing siccative.With organic filtrate and the ethyl acetate washing lotion vacuum concentration that merges, obtain yellow oil (97 gram).This oil is received in Di Iso Propyl Ether (485 milliliters) and the Virahol (100 milliliters).Be heated backflow (about 68 ℃) then.When refluxing, all substances are all dissolved, and reaction mixture is cooled to room temperature (about 20 ℃).Mixture further is cooled to 5 ℃, and after-filtration, and washs with cold Di Iso Propyl Ether (200 milliliters, 5 ℃).At 35 ℃,, obtain title compound pale solid (60 grams with the solid vacuum-drying of humidity; 52.4% productive rate).
Example 2
To [2-(7-benzyl-9-oxa--3,7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-yl) ethyl] carboxylamine tertiary butyl ester, 2,4,6-tri-methyl p-toluenesulfonate salt (173 grams; Referring to, for example, WO 2004/035592) middle Virahol (530 milliliters) and the water (175 milliliters) of adding.Add 5%w/w palladium/carbon (8.7 grams, about 60% moistening mashed prod) then.Reaction mixture is heated to 65 ℃, and hydrogenation under 3.5 crust.Reaction mixture was kept two hours at 65 ℃, then be cooled to 20 ℃; The cumulative volume that absorbs hydrogen is 7.1 liters.Remove by filter catalyzer, with Virahol (90 milliliters) washing catalyst.With organic filtrate and the Virahol catalyzer washing lotion vacuum concentration that merges, and resistates (white crystalline solid) is received in the acetonitrile (2.2 liters).To wherein adding 2-(4-cyano group-2-fluorophenoxy) ethyltoluene-4-sulphonate (103.3 grams; Referring to top preparation example B) and salt of wormwood (106.5 gram).Then with being heated backflow (about 80 ℃) about half an hour.Reaction mixture was kept eight hours at 80 ℃, then be cooled to room temperature (about 20 ℃).Filter reaction mixture, and with acetonitrile (220 milliliters) washing leaching cake.With filtrate and the filter cake washing lotion vacuum concentration that merges, and the resistates that obtains is received in the toluene (1 liter).The sodium hydroxide of water-soluble to wherein adding (280 milliliters) (31.2 gram) solution.Separate each layer, remove following (moisture) layer.Citric acid (52 gram) solution that in the organic layer that keeps, adds water-soluble (470 milliliters).Separate each layer, remove top (organic) layer.The sodium hydroxide (104 gram) and sodium-chlor (52 gram) solution that in the water layer that keeps, add ethyl acetate (1.45 liters) and water-soluble (540 milliliters).Separate each layer, remove following (moisture) layer.Sodium-chlor (17.3 gram) solution that in the organic layer that keeps, adds water-soluble (70 milliliters).Separate each layer, remove following (moisture) layer.With the dry organic layer of sal epsom (87 gram), filter, and siccative is washed with ethyl acetate (480 milliliters).With organic filtrate and the ethyl acetate filter cake washing lotion vacuum concentration that merges, obtain yellow oil (113 gram).In this oil, add Di Iso Propyl Ether (600 milliliters) and Virahol (110 milliliters), and with the extremely backflow (about 68 ℃) of this mixture heating up.When refluxing, all substances are all dissolved, and reaction mixture is cooled to room temperature (about 20 ℃).Reaction mixture further is cooled to 5 ℃, filter reaction mixture.With cold Di Iso Propyl Ether (240 milliliters, 5 ℃) washing solid.At 35 ℃,, obtain title compound pale solid (79 grams with solid vacuum-drying in baking oven of humidity; 59% productive rate).
Example 3
Final filtrate in above-mentioned two steps and washing lotion are merged, and vacuum concentration further obtains 80 gram crude product title compounds.In this crude mixture, add Di Iso Propyl Ether (530 milliliters) and Virahol (70 milliliters), obtain mixture, be heated 65 ℃ then.At 65 ℃, all substances are all dissolved, and reaction mixture is cooled to room temperature (about 20 ℃).Then mixture further is cooled to 5 ℃, and after-filtration, and with cold Di Iso Propyl Ether (70 milliliters, 5 ℃) washing solid.At 35 ℃,, obtain purifying title compound pale solid (25 grams with the solid vacuum-drying of humidity; 31.3% productive rate).
To merge by the title compound sample (be sample 1 to 3: be respectively 60 grams, 79 grams and 25 restrain) that above-mentioned three steps produce.In the mixture that merges, add Di Iso Propyl Ether (820 milliliters) and Virahol (82 milliliters).With this mixture heating up to 65 ℃, under this temperature, form solution.With reaction mixture with being cooled to room temperature (about 20 ℃) in three hours.Between 45 and 40 ℃, observe crystallization.With 20 minutes mixture further is cooled to 5 ℃, kept more than 20 minute at 5 ℃.Filter reaction mixture, and with cold Di Iso Propyl Ether (165 milliliters, 5 ℃) washing solid.At 35 ℃,, obtain recrystallization title compound pale solid (149.3 grams with the solid vacuum-drying of humidity; 91% productive rate).
1H-NMR(CDCl 3，300MHz)δH?7.49-7.29(m，2H)，7.16-6.94(m，1H)，6.31-6.02(m，1H)，4.57-4.21(m，2H)，3.93-3.82(m，2H)，3.28-3.07(m，2H)，3.05-2.87(m，2H)，2.85-2.62(m，8H)，2.49-2.37(m，2H)，1.43(s，9H)。
Scheme 3
To [2-(7-benzyl-9-oxa--3,7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-yl) ethyl] carboxylamine tertiary butyl ester, 2,4,6-tri-methyl p-toluenesulfonate salt (60 grams; Referring to, for example, WO 2004/035592) middle Virahol (92 milliliters) and water (30 milliliters) solution of adding.To wherein adding 5%w/w palladium/carbon (2.4 grams, 61% moistening mashed prod).Reaction mixture is heated to 65 ℃, and hydrogenation under 2.5 crust.Reaction mixture was kept 20 minutes at 65 ℃, then be cooled to 20 ℃; The cumulative volume that absorbs hydrogen is 2.2 liters.Remove by filter catalyzer, with Virahol (31 milliliters) washing catalyst.Organic filtrate and Virahol catalyzer washing lotion are merged.To wherein adding 2-(4-cyano group-2-fluorophenoxy) ethyltoluene-4-sulphonate (35.1 grams; Referring to top preparation example B) and the yellow soda ash of water-soluble (186 milliliters) (63 gram) solution.Reaction mixture is heated to 75 ℃, about 1 ℃ of per minute.Reaction mixture was kept 12 hours at 75 ℃, be cooled to 20 ℃ then, about 1 ℃ of per minute.(less than 50 ℃) reduces the reaction mixture volume by underpressure distillation, removes about 150 milliliters of solvents.In remaining reaction mixture, add toluene (175 milliliters), temperature of reaction is adjusted to 30 ℃, and under this temperature, keeps, till extracting the aftertreatment end.Sodium hydroxide (10.8 gram) solution that in toluene solution, adds water-soluble (98 milliliters).Separate each layer, remove down (moisture) layer.Citric acid (18.0 gram) solution that in the organic layer that keeps, adds water-soluble (162 milliliters).Separate each layer, remove top (organic) layer.The sodium hydroxide (36 gram) and sodium-chlor (18 gram) solution that in the water layer that keeps, add 4-methylpent-2-alcohol (210 milliliters) and water-soluble (186 milliliters).Separate each layer, remove down (moisture) layer.Sodium-chlor (6 gram) solution that in the organic layer that keeps, adds water-soluble (24 milliliters).Separate each layer, remove down (moisture) layer.Reduce the volume of mixture (, causing removing about 55 milliliters of solvents) that obtains less than 70 ℃ by underpressure distillation.Then it is filled in the clean container, with 4-methyl-penta-2-alcohol (30 milliliters) washing.Reduce volume of mixture by underpressure distillation (less than 70 ℃), remove about 155 milliliters of solvents.In resistates, add Di Iso Propyl Ether (560 milliliters), keep temperature to be higher than 55 ℃ simultaneously.Mixture is cooled to 20 ℃, and about 0.25 ℃ of per minute kept about 16 hours at 20 ℃ then.Mixture is cooled to 5 ℃, and about 0.25 ℃ of per minute kept about one hour at 5 ℃.Filter reaction mixture, and with cold Di Iso Propyl Ether (125 milliliters, 5 ℃) washed product.At 35 ℃,, obtain title compound white crystalline solid (29 grams, 63% productive rate) with about 22 hours of the solid vacuum-drying of humidity.
If necessary, can use following method, title compound is carried out recrystallization.
To (2-{7-[2-(4-cyano group-2-fluorophenoxy) ethyl]-9-oxa--3,7-diazabicyclo-[3.3.1] ninth of the ten Heavenly Stems-3-yl } ethyl) add Di Iso Propyl Ether (820 milliliters) and Virahol (82 milliliters) in the carboxylamine tertiary butyl ester (164 gram).With this mixture heating up to 65 ℃, under this temperature, form solution then.Reaction mixture is cooled to room temperature (about 20 ℃).Between 45 and 40 ℃, observe crystallization.Then mixture further is cooled to 5 ℃, and after-filtration, and with cold Di Iso Propyl Ether (165 milliliters, 5 ℃) washing solid.At 35 ℃,, obtain recrystallization title compound (149.3 grams with about 18 hours of the solid vacuum-drying of humidity; 91%).
1H?NMR(400MHz，CD 3OD)：δ7.53(d，J＝9.8Hz，2H)，7.29(t，J＝8.2Hz，1H)，4.38(t，J＝5.9Hz，2H)，3.89-3.82(m，2H)，3.17(t，J＝6.3Hz，2H)，3.01(d，J＝11.5Hz，2H)，2.86(d，J＝11.3Hz，2H)，2.78(t，J＝6.0Hz，2H)，2.67-2.60(m，2H)，2.60-2.53(m，2H)，2.39(t，J＝6.2Hz，2H)，1.41(s，9H)。
Scheme 4
To [2-(7-benzyl-9-oxa--3,7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-yl) ethyl] carboxylamine tertiary butyl ester, 2,4,6-tri-methyl p-toluenesulfonate salt (60 grams; Referring to, for example, WO 2004/035592) middle Virahol (90 milliliters) and water (30 milliliters) solution of adding.To wherein adding 5%w/w palladium/carbon (2.4 grams, 61% moistening mashed prod).Reaction mixture is heated to 65 ℃, and hydrogenation under 2.5 crust.Reaction mixture was kept about 45 minutes at 65 ℃, then be cooled to 20 ℃; The cumulative volume that absorbs hydrogen is 2.2 liters.Remove by filter catalyzer, with Virahol (31 milliliters) washing catalyst.In organic filtrate that merges and Virahol catalyzer washing lotion, add 2-(4-cyano group-2-fluorophenoxy) ethyltoluene-4-sulphonate (35.1 grams; Referring to top preparation example B) and the yellow soda ash of water-soluble (186 milliliters) (63 gram) solution.Reaction mixture is heated to 75 ℃, and about 1 ℃ of per minute kept 12 hours under this temperature then, then was cooled to 20 ℃ (about 1 ℃ of per minutes).(less than 50 ℃) reduces the reaction mixture volume by underpressure distillation, removes about 140 milliliters of solvents.In remaining reaction mixture, add toluene (172 milliliters), temperature of reaction is adjusted to 30 ℃, and under this temperature, keeps, till extracting the aftertreatment end.Sodium hydroxide (10.8 gram) solution that in toluene solution, adds water-soluble (97 milliliters).Separate each layer, remove down (moisture) layer.Repeat this extraction once more with aqueous sodium hydroxide solution, remove following (moisture) layer once more.Citric acid (18 gram) solution that in the organic layer that keeps, adds water-soluble (162 milliliters).Separate each layer, remove top (organic) layer.The sodium hydroxide (36 gram) and sodium-chlor (18 gram) solution that in the water layer that keeps, add ethyl acetate (210 milliliters) and water-soluble (186 milliliters).Separate each layer, remove following water layer.Sodium-chlor (6 gram) solution that in the organic layer that keeps, adds water-soluble (24 milliliters).Separate each layer, remove following water layer.With organic layer sal epsom (30 gram) drying that keeps.Remove by filter inoganic solids, with ethyl acetate (30 milliliters) washing.Under less than 50 ℃ of conditions,, obtain water white oil (40 gram) with filtrate and the washing lotion vacuum concentration that merges.To wherein adding Di Iso Propyl Ether (175 milliliters) and Virahol (35 milliliters).With this mixture heating up to 65 ℃, about 1 ℃ of per minute.Then temperature was kept 15 minutes at 65 ℃.Then mixture is cooled to 20 ℃ (about 0.25 ℃ of per minutes), kept about 16 hours, be cooled to 5 ℃ (about 0.25 ℃ of per minutes) then, then under this outlet temperature, kept about one hour at 20 ℃.Filter reaction mixture, and with cold Di Iso Propyl Ether (36 milliliters, 5 ℃) washing solid.At 35 ℃,, obtain title compound white solid (28.2 grams with the solid vacuum-drying of humidity; 61% productive rate).
Scheme 5
To [2-(7-benzyl-9-oxa--3,7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-yl) ethyl] carboxylamine tertiary butyl ester, 2,4,6-tri-methyl p-toluenesulfonate salt (300 grams; Referring to, for example, WO 2004/035592) middle Virahol (460 milliliters) and the water (150 milliliters) of adding.In the mixture that obtains, add 5%w/w palladium/carbon (12 grams, about 60% moistening mashed prod).Then with mixture heating up to 65 ℃, and hydrogenation under 2.5 crust.Reaction mixture was kept about 20 minutes at 65 ℃, then be cooled to 20 ℃; The cumulative volume that absorbs hydrogen is 11.4 liters.Remove by filter catalyzer, with Virahol (150 milliliters) washing.Organic filtrate and Virahol catalyzer washing lotion are merged.To wherein adding 2-(4-cyano group-2-fluorophenoxy) ethyltoluene-4-sulphonate (175.5 grams; Referring to top preparation example B) and the yellow soda ash of water-soluble (930 milliliters) (315 gram) solution.Reaction mixture is heated to 75 ℃, under this temperature, it was kept 12 hours, then be cooled to 20 ℃.(less than 50 ℃) reduces the reaction mixture volume by underpressure distillation, removes about 650 milliliters of solvents.In remaining reaction mixture, add toluene (860 milliliters), temperature of reaction is adjusted to 30 ℃, and under this temperature, keeps, till extracting the aftertreatment end.Sodium hydroxide (54 gram) solution that in toluene solution, adds water-soluble (485 milliliters).Separate each layer, remove down (moisture) layer.Sodium hydroxide (54 gram) solution that in (organic) solution that keeps, adds water-soluble (485 milliliters).Separate each layer, remove down (moisture) layer.Citric acid (90 gram) solution that in (organic) layer that keeps, adds water-soluble (810 milliliters).Separate each layer, remove top (organic) layer.The sodium hydroxide (180 gram) and sodium-chlor (90 gram) solution that in (moisture) layer that keeps, add ethyl acetate (1.05 liters) and water-soluble (930 milliliters).Separate each layer, remove down (moisture) layer.Sodium-chlor (30 gram) solution that in (organic) layer that keeps, adds water-soluble (120 milliliters).Separate each layer, remove down (moisture) layer.With dry (organic) layer that keeps of sal epsom (150 gram).Remove by filter inoganic solids, with ethyl acetate (150 milliliters) washing.Under less than 50 ℃ of conditions,, obtain crude product title compound yellow solid (201 gram) with filtrate and the washing lotion vacuum concentration that merges.
Further the triplicate above-mentioned steps is (once with 300 gram [2-(7-benzyls-9-oxa--3,7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-yl) ethyl] carboxylamine tertiary butyl ester 2,4,6-tri-methyl p-toluenesulfonate ester begins, the crude product title compound of 200,304 and 300 grams batch is provided twice usefulness, 450 these materials of gram).
Above-mentioned four batches crude product title compound (0.2 kilogram, 0.2 kilogram, 0.3 kilogram and 0.3 kilogram) is merged.Di Iso Propyl Ether (5 liters) and Virahol (1 liter) are joined in the merging material.With the mixture heating up to 65 that obtains ℃, under this temperature, form solution.With reaction mixture with being cooled to room temperature (about 20 ℃) in about six hours.Observe crystallization at about 37 ℃.For simplicity, reaction mixture was kept about 16 hours at 20 ℃.With 50 minutes reaction mixture further is cooled to 5 ℃, kept 5 minutes at 5 ℃.Filter reaction mixture, and with cold Di Iso Propyl Ether (1 liter, 5 ℃) washing solid.At 35 ℃,, obtain purifying title compound off-white color solid (741 grams with the solid vacuum-drying of humidity; 74% productive rate).
1H?NMR(400MHz，CD 3OD)：δ7.53(d，J＝9.5Hz，2H)，7.30(d，J＝8.2Hz，1H)，4.38(t，J＝5.9Hz，2H)，3.88-3.82(m，2H)，3.17(t，J＝6.2Hz，1H)，3.01(d，J＝11.2Hz，2H)，2.86(d，J＝12.1Hz，2H)，2.78(t，J＝5.8Hz，2H)，2.67-2.60(m，2H)，2.60-2.54(m，2H)，2.39(t，J＝6.2Hz，2H)，1.37(s，9H)。
Scheme 6
To [2-(7-benzyl-9-oxa--3,7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-yl) ethyl] carboxylamine tertiary butyl ester 2,4,6-tri-methyl p-toluenesulfonate ester (30 grams; Referring to WO 2004/035592) middle Virahol (46 milliliters) and water (15 milliliters) solution of adding.To wherein adding 5%w/w palladium/carbon (1.2 grams, 61% moistening mashed prod).Reaction mixture is heated to 65 ℃, and hydrogenation under 2.5 crust.Reaction mixture was kept 20 minutes at 65 ℃, then be cooled to 20 ℃; The cumulative volume that absorbs hydrogen is 1.1 liters.Remove by filter catalyzer, use Virahol (15 milliliters) washing then.Organic filtrate and Virahol catalyzer washing lotion are merged.To wherein adding 2-(4-cyano group-2-fluorophenoxy) ethyltoluene-4-sulphonate (17.55 grams; Referring to top preparation example B) and the yellow soda ash of water-soluble (93 milliliters) (5.94 gram) solution.Reaction mixture is heated to 75 ℃, about 1 ℃ of per minute.Reaction mixture was kept 12 hours at 75 ℃, be cooled to 20 ℃ then, about 1 ℃ of per minute.(less than 50 ℃) reduces the reaction mixture volume by underpressure distillation, removes about 60 milliliters of solvents.In remaining reaction mixture, add toluene (75 milliliters), temperature of reaction is adjusted to 30 ℃, and under this temperature, keeps, till extracting the aftertreatment end.Sodium hydroxide (3.6 gram) solution that in toluene solution, adds water-soluble (32 milliliters).Separate each layer, remove down (moisture) layer.Citric acid (9 gram) solution that in the organic layer that keeps, adds water-soluble (81 milliliters).Separate each layer, remove top (organic) layer.The sodium hydroxide (18 gram) and sodium-chlor (9 gram) solution that in the water layer that keeps, add 4-methyl-penta-2-alcohol (104 milliliters) and water-soluble (93 milliliters).Separate each layer, remove down (moisture) layer.Sodium-chlor (3 gram) solution that in the organic layer that keeps, adds water-soluble (12 milliliters).Separate each layer, remove down (moisture) layer.Reduce the volume of mixture (, causing removing about 15 milliliters of solvents) that obtains less than 70 ℃ by underpressure distillation.Then it is filled in the clean container, with 4-methyl-penta-2-alcohol (15 milliliters) washing.Reduce volume of mixture by underpressure distillation (less than 70 ℃), remove about 90 milliliters of solvents.In resistates, add Di Iso Propyl Ether (280 milliliters), keep temperature to be higher than 40 ℃ simultaneously.With mixture reheat to 55 ℃, then be cooled to 20 ℃ (about 0.25 ℃ of per minutes), under this temperature, it was kept about 14 hours.Mixture is cooled to 5 ℃ then, about 0.25 ℃ of per minute, 5 ℃ of maintenances about two hours.Filter reaction mixture, and with cold Di Iso Propyl Ether (62 milliliters, 5 ℃) washing leaching cake.With the solid vacuum-drying (at 35 ℃, about 22 hours) of humidity, obtain title compound white crystalline solid (17.8 grams, 77% productive rate).
Scheme 7
To [2-(7-benzyl-9-oxa--3,7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-yl) ethyl] carboxylamine tertiary butyl ester, 2,4,6-tri-methyl p-toluenesulfonate salt (101 grams; Referring to WO 2004/035592) middle Virahol (152 milliliters) and water (50 milliliters) solution of adding.To wherein adding 5%w/w palladium/carbon (4 grams, 61% moistening mashed prod).Reaction mixture is heated to 65 ℃, and hydrogenation under 2.5 crust.Reaction mixture was kept about one hour at 65 ℃, then be cooled to 20 ℃; The cumulative volume that absorbs hydrogen is 3.8 liters.Remove by filter catalyzer, with Virahol (50 milliliters) washing.Organic filtrate and Virahol catalyzer washing lotion are merged.To wherein adding 2-(4-cyano group-2-fluorophenoxy) ethyltoluene-4-sulphonate (58.95 grams; Referring to top preparation example B) and the yellow soda ash of water-soluble (310 milliliters) (20.01 gram) solution.Reaction mixture is heated to 75 ℃.Reaction mixture was kept 12 hours at 75 ℃, be cooled to 20 ℃ then.Reduce the reaction mixture volume by underpressure distillation (less than 45 ℃), remove about 210 milliliters of solvents.In remaining reaction mixture, add toluene (290 milliliters), temperature of reaction is adjusted to 30 ℃, and under this temperature, keeps, till extracting the aftertreatment end.Sodium hydroxide (18.01 gram) solution that in toluene solution, adds water-soluble (162 milliliters).Separate each layer, remove down (moisture) layer.Sodium hydroxide (18.18 gram) solution that in the organic layer that keeps, adds water-soluble (162 milliliters).Separate each layer, remove down (moisture) layer.Citric acid (30.15 gram) solution that in the organic layer that keeps, adds water-soluble (270 milliliters).Separate each layer, remove top (organic) layer.The sodium hydroxide (60.32 gram) and sodium-chlor (30.27 gram) solution that in the water layer that keeps, add 4-methyl-penta-2-alcohol (350 milliliters) and water-soluble (310 milliliters).Separate each layer, remove down (moisture) layer.Sodium-chlor (10.07 gram) solution that in the organic layer that keeps, adds water-soluble (40 milliliters).Separate each layer, remove down (moisture) layer.Reduce by the volume of underpressure distillation (, causing removing about 180 milliliters of solvents), be filled in the clean container, use 4-methyl-penta-2-alcohol (50 milliliters) washing then the mixture that obtains less than 60 ℃.Reduce volume of mixture by underpressure distillation (less than 60 ℃), remove about 124 milliliters of solvents.In resistates, add Di Iso Propyl Ether (935 milliliters), keep temperature to be higher than 55 ℃ simultaneously.Mixture is cooled to 20 ℃, is cooled to 5 ℃ then, under this temperature, it was kept about one hour.Filter reaction mixture, and with cold Di Iso Propyl Ether (200 milliliters, 5 ℃) washed product.At 35 ℃,, obtain title compound white crystalline solid (51.4 grams, 66% productive rate) with about 25 hours of the solid vacuum-drying of humidity.
1H?NMR(400MHz，CD 3OD)：δ7.50(d，J＝9.5Hz，2H)，7.27(t，J＝8.3Hz，1H)，4.36(t，J＝5.8Hz，2H)，3.83(t，J＝3.5Hz，2H)，3.15(t，J＝6.2Hz，2H)，2.99(d，J＝11.5Hz，2H)，2.84(d，J＝11.3Hz，2H)，2.76(t，J＝6.0Hz，2H)，2.66-2.50(m，4H)，2.37(t，J＝6.3Hz，2H)，1.36(s，9H)。
Embodiment 3
(3-{7-[3-(4-cyano-benzene oxygen) propyl group]-9-oxa--3,7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3- Base } propyl group) the carboxylamine tertiary butyl ester, the L-tartrate
To [3-(7-benzyl-9-oxa--3,7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-yl) propyl group] carboxylamine tertiary butyl ester, 4-closilate (50.20 grams, 88.36 mmoles; Referring to top preparation example C) the middle mixture that adds propan-2-ol (150 milliliters) and water (50 milliliters), then add 5% palladium/carbon (2.53 grams, 5%rel.wt., about 60% water-wet mashed prod).With the mixture hydrogenation under 2.5 crust that obtains, and be heated to 50 ℃ immediately.In case reaction has absorbed the hydrogen of required quantity, and it is cooled to room temperature.(1: 1 methylene dichloride: solvent X, potassium permanganate dyes TLC, X=80: 18: 2 chloroforms: methyl alcohol: 35% ammoniacal liquor) show to react and finish.Remove by filter catalyzer, with propan-2-ol (75 milliliters) washing.In filtrate that obtains and catalyzer washing lotion, add 1M aqueous sodium carbonate (115 milliliters).With the mixture heating up to 55 that obtains ℃, add 3-(4-cyano-benzene oxygen) propyl group 4-toluene-sulphonate (30.71 grams, 92.67 mmoles; Referring to top preparation example D).Provide mixture, then with its reflux 4 hours.TLC (1: 1 methylene dichloride: X) finish by the demonstration reaction.Underpressure distillation removes and desolvates (236 milliliters), keeps temperature to be lower than 50 ℃.Add toluene (220 milliliters) and 1M sodium hydroxide (100 milliliters), and the mixture that obtains is cooled to room temperature, then further add toluene (30 milliliters) and 1M sodium hydroxide (50 milliliters).Separate each phase, and 10%w/w citric acid (250 milliliters) is joined in the organic phase of reservation.After at room temperature stirring together 15 minutes, separate each phase once more.Add isopropyl acetate (550 milliliters) and 5M sodium hydroxide (150 milliliters) to the aqueous phase that keeps.At room temperature stirred then 10 minutes.Separate each phase once more, and wash the organic phase that keeps with 20%w/w sodium chloride solution (50 milliliters).Underpressure distillation removes from organic phase and desolvates (100 milliliters), keeps temperature to be lower than 50 ℃.Remaining mixture is filtered, add the heat extraction insoluble substance simultaneously, then it is washed with isopropyl acetate (50 milliliters).(in this step, if necessary, concentrate by the filtrate that will obtain, can separate neutral form (3-{7-[3-(4-cyano-benzene oxygen) propyl group]-9-oxa--3,7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-yl }-propyl group) the carboxylamine tertiary butyl ester).With this solution reheat to 50 ℃, then add dissolving (by heating) L-tartrate (13.42 grams, 88.52 mmoles) in ethanol (150 milliliters) with 30 fens clock times.The mixture that obtains is cooled to room temperature, causes product crystallization from solution.Solution is cooled to 5 ℃, filters and collect product, with isopropyl acetate (150 milliliters) washing leaching cake.Product is dry on strainer as far as possible, and vacuum drying (40 ℃, 24 hours) obtains subtitle compounds white solid (44.00 grams, 73.99 mmoles, 84%) then.
1H?NMR(400MHz，CD 3OD)δ7.65(dd，J＝6.9，1.8Hz，2H)，7.06-7.02(m，2H)，4.38(s，2H)，4.19(s，2H)，4.14(t，J＝6.0Hz，2H)，3.51(d，J＝12.3Hz，2H)，3.27(s，1H)，3.11(t，J＝5.9Hz，4H)，3.02(t，J＝7.9Hz，2H)，2.90(d，J＝11.8Hz，2H)，2.64(t，J＝6.2Hz，2H)，2.24(dd，J＝10.1，5.8Hz，2H)，1.74(t，J＝6.0Hz，2H)，1.45(s，9H)。
1H NMR (400MHz, D 2O) δ 7.75 (d, J=9.0Hz, 2H), 7.11 (d, J=8.7Hz, 2H), 4.53 (s, 2H), 4.30 (s, 2H), 4.24 (t, J=5.6Hz, 3H), 3.57 (d, J=12.6Hz, 2H), 3.40 (d, J=12.3Hz, 2H), 3.12 (d, J=12.3Hz, 2H), 3.01 (t, J=7.2Hz, 4H), 2.94 (t, J=6.2Hz, 3H), 2.63 (t, J=7.2Hz, 2H), 2.21 (quintet, J=6.5Hz, 2H), 1.66 (q, J=6.7Hz, 2H), 1.43 (d, J=10.8Hz, 9H).
Abbreviation
The Et=ethyl
The eq=equivalent
H=hour
The IPA=Virahol
The IPE=diisopropyl ether
The Me=methyl
MIBC=4-methyl-2-amylalcohol
The MIBK=methyl iso-butyl ketone (MIBK)
Min.=minute
The MPa=megapascal (MPa)
The palladium of Pd/C=on carbon
The platinum of Pt/C=on carbon
The TLC=thin-layer chromatography
Prefix n-, s-, i-, t-and tert-have its implication commonly used: just, secondary, different and uncle.

Claims (26)

1. the method for the sulfonate of preparation formula I or its solvate,
Figure S2006800222462C00011
R wherein 1Expression C 1-6Alkyl (optional) or aryl by the replacement of the substituting group of one or more being selected from-OH, halogen, cyano group, nitro and aryl;
D represents the C of optional branching 2-6Alkylidene group, condition are that it does not represent 1,1-C 2-6Alkylidene group;
R 2Represent unsubstituted C 1-4Alkyl, C 1-4Perfluoroalkyl or phenyl, the group of back is optional by one or more C that are selected from 1-6Alkyl, halogen, nitro and C 1-6The substituting group of alkoxyl group replaces; With
Wherein each aryl is optional the replacement, unless otherwise mentioned;
This method comprises: basically by water, C 3-5Secondary alkyl alcohol exists down with the solvent systems that the another kind of organic solvent that is no more than 15%v/v is formed, with sulfonate or its solvate hydrogenation of formula II,
Figure S2006800222462C00012
R wherein 3Expression is for the amino protecting group of destabilizing hydride, R 1, R 2With D as mentioned above.
2. the desired method of claim 1 is wherein implemented this method, so that basically by water, C 3-5The salts solution of formula I is provided in the solvent systems of secondary alkyl alcohol and the another kind of organic solvent composition that is no more than 20%v/v.
3. the method for preparation formula IX compound or its pharmacy acceptable derivates,
Figure S2006800222462C00021
Wherein
R 1With D such as claim 1 definition;
R 6Expression H, halogen, C 1-6Alkyl ,-OR 9,-E-N (R 10) R 11, or and R 7Expression=O together;
R 7Expression H, C 1-6Alkyl or and R 6Together, expression=O;
R 9Expression H, C 1-6Alkyl ,-the E-aryl ,-E-Het 1,-C (O) R 12a,-C (O) OR 12bOr-C (O) N (R 13a) R 13b
R 10Expression H, C 1-6Alkyl ,-the E-aryl ,-E-Het 1,-C (O) R 12a,-C (O) OR 12b,-S (O) 2R 12cC ,-[(O)] pN (R 13a) R 13bOr-C (NH) NH 2
R 11Expression H, C 1-6Alkyl ,-the E-aryl or-C (O) R 12d
When using herein, R 12aTo R 12dWhen occurring, represent C independently at every turn 1-6Alkyl is (optional by one or more halogen, aryl and Het of being selected from 2Substituting group replace), aryl, Het 3, or R 12aAnd R 12dRepresent H independently;
When using herein, R 13aAnd R 13bWhen occurring, represent H or C independently at every turn 1-6Alkyl is (optional by one or more halogen, aryl and Het of being selected from 4Substituting group replace), aryl, Het 5, or represent C together 3-6Alkylidene group, optional by the O atomic separation;
When using herein, E represents direct key or C at every turn when occurring 1-4Alkylidene group;
P represents 1 or 2;
A represent direct key ,-J-,-J-N (R 14a)-,-J-S (O) 2N (R 14b)-,-J-N (R 14c) S (O) 2-or-J-O-(in four groups of back ,-J is connected with the two pyridine ring nitrogen of oxa-);
B represents-Z-{[C (O)] aC (H) (R 15a) b-,-Z-[C (O)] cN (R 15b)-,-Z-N (R 15c) S (O) 2-,-Z-S (O) 2N (R 15d)-,-Z-S (O) n-,-Z-O-(in six groups of back, Z with have a R 6And R 7Carbon atom be connected) ,-N (R 15e)-Z-,-N (R 15f) S (O) 2-Z-,-S (O) 2N (R 15g)-Z-or-N (R 15h) C (O) O-Z-(in four groups of back, Z and R 8Group is connected);
J represents C 1-6Alkylidene group, its optional quilt-S (O) 2N (R 14d)-or-N (R 14e) S (O) 2-at interval, and/or optional by one or more being selected from-OH, halogen and amino substituting group replacement;
Z represents direct key or C 1-4Alkylidene group, optional quilt-N (R 15i) S (O) 2-or-S (O) 2N (R 15j)-at interval;
A, b and c represent 0 or 1 independently;
N represents 0,1 or 2;
When using herein, R 14aTo R 14eWhen occurring, represent H or C independently at every turn 1-6Alkyl;
R 15aExpression H, or and R 8Single ortho-substituent on the group (ortho position-connect with respect to the B group position) together, R 15aExpression C 2-4Alkylidene group, it is optional by O, S, N (H) or N (C 1-6Alkyl) at interval or be terminal;
R 15bExpression H, C 1-6Alkyl or and R 8Single ortho-substituent on the group (ortho position-connect with respect to the B group position) together, R 15bExpression C 2-4Alkylidene group;
When using herein, R 15cTo R 15jWhen occurring, represent H or C independently at every turn 1-6Alkyl;
R 8Expression phenyl or pyridyl, two groups all choose by one or more and are selected from following substituting group replacement :-OH, cyano group, halogen, nitro, C 1-6Alkyl is (optional with-N (H) C (O) OR 16aBe terminal), C 1-6Alkoxyl group ,-N (R 17a) R 17b,-C (O) R 17c,-C (O) OR 17d,-C (O) N (R 17e) R 17f,-N (R 17g) C (O) R 17h,-N (R 17i) C (O) N (R 17j) R 17k,-N (R 17m) S (O) 2R 16b,-S (O) 2N (R 17n) R 16o,-S (O) 2R 16c,-OS (O) 2R 16dAnd/or aryl;
And ortho-substituent (ortho position-with respect to the tie point of B) can
(i) and R 15aRepresent C together 2-4Alkylidene group, optional by O, S, N (H) or N (C 1-6Alkyl) at interval or be terminal, or
(ii) with R 15bRepresent C together 2-4Alkylidene group;
R 16aTo R 16dRepresent C independently 1-6Alkyl;
R 17aAnd R 17bRepresent H, C independently 1-6Alkyl, or represent C together 3-6Alkylidene group forms four to seven yuan and contains azo-cycle;
R 17cTo R 17oRepresent H or C independently 1-6Alkyl; With
When using herein, Het 1To Het 5When occurring, represent five to ten binary heterocyclic groups independently at every turn, this heterocyclic group contains one or more heteroatomss that are selected from oxygen, nitrogen and/or sulphur, and this heterocyclic group is optional to be selected from following substituting group and to replace by one or more :=O ,-OH, cyano group, halogen, nitro, C 1-6Alkyl, C 1-6Alkoxyl group, aryl, aryloxy ,-N (R 18a) R 18b,-C (O) R 18c,-C (O) OR 18d,-C (O) N (R 18e) R 18f,-N (R 18g) C (O) R 18h,-S (O) 2N (R 18i) (R 18j) and/or-N (R 18k) S (O) 2R 18l
R 18aTo R 18lRepresent C independently 1-6Alkyl, aryl or R 18aTo R 18kRepresent H independently;
Condition is:
(a) work as R 7Expression H or C 1-6Alkyl; Represent with A-J-N (R 14a)-or-during J-O-, so:
(i) J does not represent C 1Alkylidene group or 1,1-C 2-6Alkylidene group; With
(ii) B does not represent-N (R 15b)-,-N (R 15c) S (O) 2-,-S (O) n-,-O-,-N (R 15e)-Z ,-N (R 15f) S (O) 2-Z-or-N (R 15h) C (O) O-Z-; With
(b) work as R 2Expression-OR 9Or-E-N (R 10) R 11, when wherein E represents direct key, so:
(i) A do not represent direct key ,-J-N (R 14a)-,-J-S (O) 2-N (R 14b)-or-J-O-; With
(ii) B does not represent-N (R 15b)-,-N (R 15c) S (O) 2-,-S (O) n-,-O-,-N (R 15e)-Z ,-N (R 15f) S (O) 2-Z-or-N (R 15h) C (O) O-Z-; With
(c) represent-J-N (R as A 14c) S (O) 2In-time, J does not represent C so 1Alkylidene group or 1,1-C 2-6Alkylidene group; With
(d) work as R 3Expression H or C 1-6Alkyl and A represent-J-S (O) 2N (R 14b)-time, B does not represent-N (R so 15b)-,-N (R 15c) S (O) 2-,-S (O) n-,-O-,-N (R 15e)-Z-,-N (R 15f) S (O) 2-Z-or-N (R 15h) C (O) O-Z-; With
Wherein each aryl and aryloxy are optional the replacements, unless otherwise mentioned;
This method comprises:
(I) basically by water, C 3-5Secondary alkyl alcohol exists down with the solvent systems that the another kind of organic solvent that is no more than 15%v/v is formed, with sulfonate or its solvate hydrogenation of formula II,
Figure S2006800222462C00041
R wherein 1, R 2, R 3With D as mentioned above and
(II) it need not be separated, with the sulfonate of the formula I that forms thus,
R wherein 1With D such as claim 1 definition
With alkali and
(a) compound of formula X reaction,
L wherein 3The expression leavings group, R 6, R 7, R 8, A and B as mentioned above, or
(b) represent C for A wherein 2Alkylidene group, R 2And R 3The compound of the formula IX of expression=O group together, with the compound reaction of formula XI,
R wherein 8With B as mentioned above, or
(c) represent CH for A wherein 2, R 6Expression-OH or-N (H) R 10The compound of formula IX, with the compound reaction of formula XII,
Figure S2006800222462C00054
Wherein Y represent-O-or-NR 10-, R 6, R 8, R 10With B as mentioned above,
Wherein the reaction with formula X, XI or XII is to comprise water and C 3-5Carry out under the existence of the solvent systems of secondary alkyl alcohol.
4. the desired method of each of aforementioned claim, wherein C 3-5Secondary alkyl alcohol is a Virahol.
5. the desired method of each of aforementioned claim, the salt of its Chinese style I are the catalytic hydrogenation preparations of the salt of through type II.
6. the desired method of each of aforementioned claim, the hydrogenation of the salt of its Chinese style II is being carried out more than 35 ℃ or 35 ℃.
7. the desired method of each of aforementioned claim, wherein R 1Represent saturated C 1-6Alkyl.
8. the desired method of claim 6, wherein R 1The expression tertiary butyl.
9. the desired method of each of aforementioned claim, wherein R 2The expression phenyl, optional by one or more substituting groups replacements that are selected from methyl, halogen and nitro.
10. the desired method of claim 9, wherein R 2Expression 2,4, the 6-trimethylphenyl.
11. the desired method of each of aforementioned claim, wherein R 3The expression benzyl optional be selected from following substituting group and replace by one or more :-OH, cyano group, halogen, nitro, C 1-6Alkyl, C 1-6Alkoxyl group ,-N (R 4a) R 4b,-C (O) R 4c,-C (O) OR 4d,-C (O) N (R 4e) R 4f,-N (R 4g) C (O) R 4h,-N (R 4i) S (O) 2R 5a,-S (O) 2R 5bAnd/or-OS (O) 2R 5c, R wherein 4aAnd R 4bRepresent H, C independently 1-6Alkyl or represent C together 3-6Alkylidene group forms four to seven yuan and contains azo-cycle, R 4cTo R 4iRepresent H or C independently 1-6Alkyl, R 5aTo R 5cRepresent C independently 1-6Alkyl.
12. the desired method of claim 11, wherein R 3Represent unsubstituted benzyl.
13. the desired method of claim 1 is wherein implemented this method, so that the salt of formula Ia or Ib is provided,
Figure S2006800222462C00071
R wherein 1As claim 1,5 or 6 each define.
14. the desired method of claim 3, administration step (I) wherein, so that the salt of formula Ia or Ib is provided,
Figure S2006800222462C00072
R wherein 1As claim 1,5 or 6 each define.
15. the desired method of each of aforementioned claim, wherein hydrogenation is to carry out under the situation that does not have external acid and/or alkali.
16. claim 3 to 12, each desired method of 14 and 15, wherein employed alkali is alkaline carbonate in the step (II).
17. the desired method of claim 16, wherein alkali is salt of wormwood or yellow soda ash.
18. each desired method of claim 3 to 12 and 14 to 17, wherein the reaction of step (II) is to carry out between the salt of formula I and the defined formula XII compound of claim 3.
19. the desired method of claim 18, the compound of its Chinese style XII are 4-(epoxy ethyl methoxyl group) benzonitriles.
20. each desired method of claim 3 to 12 and 14 to 19, the structure fragment of the formula IXa of the formula IX compound of wherein final preparation,
Figure S2006800222462C00081
Representative:
Figure S2006800222462C00082
21. each desired method of claim 3 to 12 and 14 to 17, wherein the reaction of step (II) is to carry out between the salt of formula I and the defined formula X compound of claim 3.
22. the desired method of claim 21, the compound of its Chinese style X are 4-(2-bromine oxethyl)-3-fluoro benzonitrile or 2-(4-cyano group-2-fluorophenoxy) ethyltoluene-4-sulphonate.
23. claim 3 to 12, each desired method of 14 to 17,21 and 22, the structure fragment of the formula IXa of the formula IX compound of final preparation wherein,
Figure S2006800222462C00083
Representative:
24. each desired method of claim 3 to 12 and 14 to 17, wherein in the compound of the formula IX for preparing:
R 1The expression tertiary butyl;
D represents-(CH 2) 2-or-(CH 2) 3-;
R 6The expression H or-OH;
R 7Expression H;
A represents CH 2
B represents-Z-O-;
Z represents direct key or CH 2With
R 8Be illustrated in that contraposition (with respect to B) is replaced by cyano group and at the ortho position (with respect to B) by the optional phenyl that replaces of fluorine.
25. the desired method of claim 24, wherein Zhi Bei formula IX compound is selected from:
2-{7-[(2S)-3-(4-cyano-benzene oxygen)-2-hydroxypropyl]-9-oxa--3,7-diaza-two ring [3.3.1] ninth of the ten Heavenly Stems-3-yl } the ethyl carbamic acid tertiary butyl ester;
(2-{7-[2-(4-cyano group-2-fluorophenoxy) ethyl]-9-oxa--3,7-diazabicyclo-[3.3.1] ninth of the ten Heavenly Stems-3-yl } ethyl) the carboxylamine tertiary butyl ester;
(3-{7-[3-(4-cyano-benzene oxygen) propyl group]-9-oxa--3,7-diazabicyclo [3.3.1] ninth of the ten Heavenly Stems-3-yl } propyl group) the carboxylamine tertiary butyl ester,
With its salt and/or solvate.
26. basically by the following mixture of forming:
(1) aqueous solution of alkaline carbonate; With
(2) 4-(epoxy ethyl methoxyl group) benzonitrile.
CNA2006800222462A 2005-06-20 2006-06-12 Process for the preparation of N,N'-disubstituted oxabispidines Pending CN101203521A (en)

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