HU230655B1 - A method for the preparation of fingolimod - Google Patents

Description

The present invention relates to a novel process for the preparation of 2 amino-2- (2 '- t-i-octylphenyl) ethyl] propan-1,3-yl of the structural formula (Ϊ) known as F1Y 220 air mist or generically known as tingolimod.

0) the active ingredient of the Gllenya pharmaceutical formulation (bovartis) used in the deep hydrocil.orid form,

In the present description, the structural formulas of the present invention are represented by a Roman numeral in parentheses throughout the text and A 0 is always an ethyl group.

State of the art:

The production of fingoii.mod 1 according to macrometric in the images of <X) was first reported in 1995 (Adaohl K ,, Coder

T, _f Cocoa 11 ,, Arifa ib, Galba K «, Atshina T <, Sasaki S <, buére '1.3: Bioorg, Hod, Cbem. Lett, 1995, 5, 8 53-8 56). The halo derivative of formula Ha (X "Sri or XJh (X" = 1)) was digested with IXX-burnt acetic amidoethyl'-malonate to provide the corresponding intermediate of Formula XV, which further gave Formula X to fingolimod. no details of production or yield have been communicated.

P-1.419 t δ Iá. : G5,11

P15ÖQ023

ÜHyéb'bb ''

> 'ΌΕΐ

ΆηΗΝ ..... 4, Α'ΌΕΙ

0 '

ua; X Br y

Hh, X ~ |

ΕΚ, ο <.Ο

,, oO r

GCC

PHmoo (0

1, Kcaktaaéoayen i et: lake. swallow it spell it

S ypsnifoM GyPnyrzet'oyét ikbéet ;. _s Obate shoot} liSlété azéna Has the patent for her machine been patented by etsb tsljes siilé _? · Two methods were used by meei. fingoilmoő slöélli.tááára. For the synthesis shown in Table 1, but the corresponding Xlfe formula is iodine derivatives

Synthesis of W. la leleic (a .: reaction equation}, and to the last one, the formula of the starting substance V was the one from which the telxlone was saved by the VX image idea tea 1 idea Krienei ·· harvested by aellazéecel atamintam-ti sehtel aelén, the right formula for VIX is the Cetacea calf, The next step, from Vili, is the formula for 1; ke hc 11 y h | dr cl I, the me 1 yet H x 11 is 11 juice. Yiddish Ieakeidyai was given the formula XXb by Godid, in Z '04, the synthesis of a gum from a gum XXb yielded 4-? 2-dsiöt: from the phenols of oxyethid, Id, G, kaonrch .a, fnnstner A,: g. being, look,

ÓSóé'ISII ',

MA ·: nn atew

Ms {CH _s } _? COCi

AICÍ3 ~~~~~~ - ,,, Λ ---------- Ae

Et sSíH

MeÖNs

Z '?

Nsi ab

..- '' X ö SÖ> D ©. XX! « _{MeS0? C§}

I J

XX ^ x

2. Reaction equation: Synthesis of iodide XXb

According to the above-mentioned patent, the iodide of formula XXb was converted into the final product by two processes. The first process involves the reaction of iodide and XXX in the presence of sodium ethoxide with dimethylacetate dehalamate in the presence of sodium ethoxide. lein diols are formed which then, when reacted with acetic anhydride, leads to the preparation of the acetate of formula .XI. One disadvantage of this procedure is that the starting halogen derivatives are difficult to prepare (see previous paragraph.) Another disadvantage is the relatively long conversion of the ester groups to the hydroxyl-esoporates (reduction, protecting group). cleavage).

P-1419, found 2215.09.23

Pl 500023

νη ₂

Ί

OH

Reaction Equation 3: Synthesis of Fingeline Synthetic Formula XXb

An alternative process for the preparation of xinololimod of formula XXb from iodide (reaction equation 4) involves the reaction of iodide with XXX: diethyl malonate in the presence of sodium ethoxide, and the resulting compound of formula XXIX is formed with an amination reagent containing the compound of formula XXV.

The final step is the reduction of the ester groups with sodium hydroxide. Again, the starting material for the hard-to-produce iodide process XXb. which was obviously a disadvantage and again the Estonian groups were reduced to the H idroz11 group.

P-I41S

20X5 <02.23

FI500023

CHfeCHfefe

SHE,

K · '?

She

NaOEt

CHpCM?}

NaH / DMF.-Fee, .ΟΝΜ

TIN

phoenix (1)

NaSkfe

4., fieá kEl.ss g yen 1. s t s FI0 go I lsed m a t e r i n g 11 f o r o f 1 e t i t i o n t h e f i d e d

The above X11105X1 snake lanade scabfedaXfei Xeifáábfen bemdfe 'burial possibility could be the effect of one of these outli.eolae.i threat covers t _: XXX late dletii - n cdafeid ion of _f: srteiysfe ffe ffe. the XVIX kipisin doet s l.oáii .; the existence of. kot has been reduced to so dsetsr, '''XVIH-' *, 'XIX \ x x. '''''fefeiisetsk,. feo in let seating kk kfepistd ketone sinkifsti.dk pk tán ο sv - k 1 g kiddel kr 1 e P e 1 - C refteeoii et et 1 pfe, inio tv- ki o.fel o p-felenlfe tfefesfe 1 k. / tsdvksl, feefeysefesfe 1>

fesilli 10 tfen .10 oa ,, X

ο.

1 to

OGF

BO ... <. 0

XVI * AcHN \

NsOEt

-Q &

Abma

... ..,.SHE ; r

OB

Athna

OH ht

XV u xvm

CRgCH ^ CQ '·

XX

C <K

X, AnHN

Aííö ·.

OAC

Me (CH ₂ ) _g COCl

Aicha

AtHN 1.

Gae

XIX.

n, keakoiö uniform; Formula XX is a ketone synthesis

The ketone of formula XX was transformed into the formula IX) f in a different manner in the reaction equation 1 as described in Ola.Ol. In the above formula, the ketone of formula O was reduced to the resulting keto-oophor tg. : compound iX) converted to irgoismod 3

W tea ke Mountain! in five, Matt backs into the Tori way. More options''♦ 1 XX''p'> * ·. \. ^vx 'η x' ^s lie.;, .- ioot.ti.ettek., sk «pet?. XXX formula: walnuts ketc-osopoB hm reoaked, which became a XXX X image feed diet, produced by main dezaentiiezeooel, ltot cancer on IX) fmoton. Ah

P. '' x \ <xGO '.G'>'*·' B 'B rn i XX \ χ K ^f ketone tnigos dezaeethlezéao to XXXXX image to ketone,. which. (X i was reduced to idol.lmod. In his et and. Reaction equations, the famous e. E. Essentially retained the benefits shown in the 2 and the, teake 1 equations; only those steps became aorread.

> 'TááÍi

WAÖldi

AcO

-Τχ

AcHN chyew

OAS

· Λ'-

y. Equation: Synthesis of Fingolimod from Formula XX Ketone

A further procedure (X) for writing fingolimod is disclosed in a published article 2000beu (Durand Fi, Feralba P., Sierra Fi, P.enaut P. <Syntnesis. 2000, 5Q5-5OS) and described in Reaction Equation 71. The starting material is octibenzene, from which bromoacetophenone of formula XXXV 'is obtained by acylation of bromoacetyl chloride with Friedel-Crafts in the presence of aluminum chloride. This resulted in condensation of a diacetylacetamide of the formula IXX-E5a with a sodium salt of malmalate, to give a keto derivative of formula XXV, from which the intermediate XV was reduced. Synthesis of fingolimod (X) from this compound became visible in the 3rd cancer cells16. This is it. Process 4 also retained the disadvantages of the procedure shown in Reaction 3.

F-1419

Pl 500023 <X, OEt

GHsfGHsV

CHsíCHgb '

CHsfüH ^ <Ő \ / ^ .z-'yX. ^ ZG j]

SHE

CH ₅ {CH ₂ } 7

Reaction equation 7: Synthesis of intermediate XV from © kti1benzene

Further preparation is described in a publication published on 20, 4-Chlorobenzaldehyde by J. Alita S.,. Barna d., Bezbarua M., Bez G.: Syniett, 2001, 9, 1411-1414). The substituted benzaldehyde of formula XXVX was prepared by the Negishi reaction of n-octyl zinc iodide in the presence of p-chlorobenzaldehyde (R 10). The resulting aldehyde was then reacted with vinyl magnesium epoxylated and given an epoxide of SUCCXXXX which, with bgSO2-febCl2, yields a nitrodiol of formula XXXX. The latter is of the formula XXX with chloro-trimethylsilane and sodium iodide. converted to an unsaturated nitro derivative. Reduction of the double bond was accomplished by hydrogenation on a palladium on carbon catalyst and reacted with the resulting nitro derivative of Formula XXXX to afford Nitrodioid XXXII. The nitro group was reduced on Ra-catalyst to produce (X) fumarimod (reaction equation 8). Although this method is no longer necessary to convert the ester functionality to hydrosyl groups, it is a linear and relatively long-term production <25

P ~ l «19

P1.500023

'0 CB, »

MaSOá. · 'Art

2? 7

NO, TMSCi-Nsi

MpCH ₂ ) _?

Here's the 'feu''

OH

WOMAN,

2)?

pH

Ott, _K V> ö <xy. • Αν ^ · h ₂

Pd / C

XJ

WOMAN,

CH, 0

SNOW

SNOW

WOMAN·:

CttyCttgl

XJ ,, nh ₂

Ί

OH

XXXt

Nsraod (

8 ". Reaction equation: Synthesis of Fingolylisod in 4-fold z al dehi. db ο .1

In 2005, lei.rt another procedure was XWX. formula for the use of octylphenylalehea (Sugiyama S, Arai S, Kiriyama N, Ishii K, Chevu Rharm). Ball, 2005, 53, 100-102¾ of 4-acylbenzaldehyde XXVI is first obtained by the reaction of dibromide X3EKXIX with the reaction of tetrabromomethane of triphenylphosphine, which is converted to the alkene XXXXV by treatment with butyllithium. The aqueous treatment of the reaction mixture resulted in the addition of the triple bond to the boronic acid adduct resulting in the boronic acid derivative. In the next step, Betasis was reacted with dihydroxyacetone and benzylamine to give an unsaturated intermediate of XkWX. The catalyst has the disadvantage of using expensive catecholborane.

P-1413 red 2015.03.23

Pl500023

ΡΥ% C 8g Ph ₃ P 8sü ^Br Me (C «Ι v -Ήΐ /? XXVI XXX® XXW

katsehoibörsn

CHáPHs} /

ΗΟ · .NH? Pd / C> HÖCKjCOCléOH

LMHPn

- <X. 1 h ^: H i ^{5 l} l> .. ··· OH "Z \ V OH

WCCi-yf r

QH

Reaction equation 9: Synthesis of Fingolymod 4-oct _: ylbenz-1d.beta. 1 δ In a further known process, the starting material is XXXroX l-amino-z- (hydroxymethyl) propane-1,3-diol (Aris) (Kia S). , Lee H,, Lee M., Lee T ..: Synthesis, 2G6, 5, 7 53-755} _f, which first formed a protecting group on nitrogen in the form of an acetonide in the form of the B3c radical X3U £ VIt £ &gt; By swern oxidation, they were converted to the aldehyde X3CKX.X. The aldehyde was reacted with dimethyl-S-oxopropyl.lf phthalate and p-toluene sulforyls with alkyne XL, followed by Sonogashira reaction with 1-iodine ~ 4 ~ dHt.llfefonzole. of formula (II) gave the intermediate Boc-amine XLII, which was converted to the compounds of formula (II) by acidic hydrolysis (1), with the advantage that inexpensive 2-amino-2 (hydroxyethyl) propane-1,3 (Trisj was employed. Disadvantage, that the Swern oxidation of the XXXVXrXa alcohol produces the corresponding aldehyde by-products with an unpleasant odor, and the use of peteneyl XIsah as a dangerous tosyl azide.

14,13

Pl500013

XI

First

2. Soc

CÍCOCOC!

DMSO

X f NHBoc OH {f NHBoc

TsN ₀

Yeah

M

WBoc .νζ ^ χί, rf UPh ₃ P) Pd

STONE

OH: ₃ (CH ₂ ).

Cul

m) t

OH (WCH5A

X ^ h ₂ h ₂ g, h *, ··· \, .............—

NHBoe h ₂

Pe / C .xX ^ NHBoc

Reaction equation: Synthesis of Fingelomod from Tris

Another published synthesis of fingolimod (X) consists of a summary of the major known reactions (Liang 1 .: Dilin Daxue Xuebac, Lixueban, 2008, 4 6, 139-142). The first step is to acylate benzene with octanoic acid chloride according to Fcledel-Crsít. Reduction of the ketone thus obtained yields octylbenzene, which conversion to the (X) fmdrmod is only a modification of the procedure described in Reaction Equations 7 and 3.

Novartis NG2Q010111SS34 (Sedelmeier G.) was prepared starting from 2,4,4-dibromoacetofen ⁽ XbXXX), the reaction of which with formula XLXV gave ethyl ester XLXV yielded a diester. This resulted in a reaction with 1-α-Sonogeso to give alkyne Vb. The latter was hydrogenated to an intermediate of formula XV on palladium catalyst (11, Reaction equation). By converting this, the fingoolimod of formula X>, which has already been shown in many previous processes, has been obtained.

R-141S New 2015.09.23

RÍ500023

11. Reaction equation; Synthesis of intermediate XV 1 _f 4 ^? ~ dl br omm-acetophene · you have 1 more loving procedure at Xuzhou Norma! Universifcy (Wang Y., Ji G ,, Gu S., ihang X ,, ii L ,, Chen Y.) in Patent Nos. 1814583 and 100543963, respectively. The starting material for the synthesis is styrene, which was first acylated with octanoic acid chloride 10 to form intermediate VLX. yielding intermediate V & ZX by reaction of diethyl acetamidomalonate XXX; Reduction of the two groups of the pellets of the formula VX-ZZ resulted in the already known intermediate XV, the conversion of which (X) to fingolimod has been described in several previous processes.

EtO x ^ G

Box ^ yO

CH ₃ (CH ₂ ;

CH _s (CH ₂ ) _$ CO '·

Ά.GB

CH ₃ (CH _S ) _? · 'Vu

VIII

O '\, ^Z \,' ^A 11 AcHN

ARC

8-1419 .Ρ.150ΌΌ23 «0

12. Reaction equation :: Synthesis of formula XV from diethyl acetylamino derivative

Growingchec: Julia's olefin-based iaod5 is described in Chinese Patent Application 102120120 (Reng

Reng Η.): (X) for the preparation of ringd, The starting compound of formula VXXXX: (obtained by reaction of 4-octylbenzylbromide with 2-mercaptobenzo (dithiazole) - was first oxidized to the fiber by the image of XL. the next step was used in the olefinization of an aldehyde of the formula X. The unsaturated derivative of the formula L1 was hydrogenated on a palladium catalyst and the acid hydrolysis of the resulting folinogimacetonide X.XX yielded the hydrochloride salt of fingdimod. which obtained the aldehyde L of the formula by the name of Wittig 4-cktiiόβηζ1] .- ΐΓϋ © η11 “Ίθ5ζ10ηίΰΕΐ ·” 0ΓθΒίάό3ΐ to the unsaturated derivative of formula XI (Reng X., Mei Y., Inc. Y .; Monatsh. Chesn 2012, 143, l. Similarly to the procedure described in Reaction 10, the aldehyde of formula II was used, which was again

X2E8VXXX & alcohol obtained by the oxidation of Svam - also accompanied by unpleasant odor by-products.

P-1419 "Night: 23.09.2011

P1500023

vun il

you

13. Fingollmod Synthesis of Reaction Equation Julia's oil linearization further teaches that some Syrian derivatives can be opened r-egioselectively with the appropriate nucleophilic reagents to form the corresponding amino derivatives, such as 1ΠΙ-picene-sulfated atirium. opening with gfeCuLi type 10 metallostagnic derivatives in the presence of BFs.FtaO results in secondary amines of the formula LXY (Fis FL J., Ganem B .: Tetrahedren Lett. 1385, 26, 1153-6; another known option is 1 r 3-me t exi -phenyl 1 -m g spect 1 µm -b Roma iodine in the presence of 1 CuB r · te ₂ .S (Sringmann G., Bisehof S, K <, Mueiier S., Gulder

T ,, Winter e ,, Stich A ,, Heidrun M ,, Kaiser M., Brun R., Dreher J>, Baumann K .: Für, J. med. Chem. 2010, 45, 5370-5383} (14. Reaction equation1.

P-1419

F150ÖÖ23

sit

R ² ¥

R ¹ - Boc R ² = H. Mé

14, Reaction equation; Nucleophilic opening of 1,2,2-trisubstituted aziridine derivatives of formula LXXX

Mapi Pharma Ltd. WO 2012/056458 is also known! Among other things, his patent application includes, inter alia, t-butyl (2,2-dimethyl) -5- (4-octanoylstyryl) 1,3,3-dioxan-5-yl-arm brown, and t-butyl (2,2-dimethyl) - 5- (4-octyltitrile) -1, 5-dioxane-S11) carfeamate. and, by reduction thereof with sodium borohydride, followed by hydrogenation on palladium-on-carbon catalyst and removal of the resulting intermediate by the removal of ethyl acetate or ketal and the nitrogen protecting group, fingolimod,

Description of the Invention:

The present invention provides an efficient process for the synthetic preparation of fingolimod. The present invention is based on the discovery that the appropriately protected 5,? -Dioxa-azaspircp, 5] octanes of formula (LVX) can be regioselectively opened to the corresponding amino derivatives by the Grignard compounds of formula (LVXI) - in which

E ⁴ is 1-ocf 11, chlorine, bromine or iodine, and

X ¹ represents a chlorine, bromine or iodine atom, R ¹ - p? meaning is given in the detail section below. This reaction provides the appropriate monooiklusoe derivatives which can be converted to the fingolimod {15, reaction equation). The most important advantage of the fingolimod almost 25 synthesis method is the technique P-1419 "New 2015.09.23

P1500023

IX according to the state of Jan1eg1. the easy availability of starting (ΧΛ / Χ) 5,7-dioxa-1-aza-spirofz, ayoctans from inexpensive and commercially available 2-amino-1- (hydroxymethyl) -propane-1,3-ol (Trlsj.) are available this mentioned

Grignard also mixes,

Detailed Description of the Invention:

The present invention relates to a process for the preparation of phylgolimod (I) which comprises reacting an intermediate spirocyclic compound of formula (X.VX) with an aziridine moiety.

- wherein main and shoot are independently hydrogen or C1-C4 alkyl, then - is a protecting group, namely COO, where - is optionally tailored. an alkyl, optionally substituted aryl, or optionally substituted benzyl group of 1 to 6 carbon atoms to react it with an organometallic compound 1, preferably a Grignard reagent of formula (LVXX),

- in which; he ^? denotes 1-oct-1i, a chlorine, an aroma, or a power atom, and wherein

X 'is chloro, chromium ··, or iodine ~ n' .LVIXi) -ap, ', XXX) bt -ro ^c ) ο'Ί <; ui nt ^; - v \ :: s. '

- in which

R ¹ , shoot, shoot are as defined above and main ^: is chlorine, bromine, or iodine.

The ring closure with Grignard reagent is preferably carried out with the catalysis of transition elements and transition compounds, in particular copper compounds, preferably CeJ, CuBr, nBrBeG, CuCl.

P-lklü B15000023

20X6,03.16

R'Z> ···· ο.-M '>

R ⁵ X

X oot J, fc, Ή -Ρ ²

Z ''

LYi

LVItt; R '= 1-öKvi z, z iZ z ^x r

ÜX.Z z

HZ

H '

ZhyCHZ .o

Z - COOR ⁵ RCHgCHfe;

OH OH

L J is ed (|)

15. Req equation: (£ »VX> aciridine of general formula: u k 1 e f í b 2 2 2 ma é ven: x ven - ··· no 1 og s r i de k ks i

Curse of the X-robe image of iXYXXÜ XXbiZíXüni, Z dloxanos, amélyektvea r anlnne sepert aiki. i ~ or sril 's into an aborodn group;.;. seeded, by direct hydrolysis of the snow • D fisgöi imodcia aiat.Zketbk, If the protective formula of 4 -ckiXi1 Z-dioxateZ Zltogan -'- of the (LVTIl) allant is given in vinegar atebstt 1 reá11 ηεηη-οΖκΧηοΖοη

the removal of the amir-o-csepcrt yédoosoporti price and whitewashing of the hollow xlmseports from the acid bridge by xsissei (X) fingóipod,

An advantageous feature of the above process step of the present invention is the use of ethereal compounds (WXXXZ subfamily inserts).

Z Z Taste Oh, Z .11

Pl 500023

CK ₃

- in which

R ³ ' ^: represents COOR ^{s: I} in which

R * ¹ is Cercier butyl or benzyl and

R ⁴² is 1-octyl, chloro, chromium or iodine.

In another preferred embodiment of the above process step of the invention, a compound of formula (tXX ') is used.

V

O ^X O 'N-GOO-RS1

H

- in which

R ' ^J ' is selected from the group consisting of chloro, bromo, and iodo, and is a tertiary-butyl or benzyl group.

Primarily formed halogen closure of formula XXX © kot - eme1yfeen

R * ^A is a chlorine, bromine or iodine atom, and R ¹ , R ² , R 'are as defined above - is further converted to a 4-position substituted phenyl-ethyl group in one step (XX) with an organometallic reagent or in two steps to Sonogashira's reaction. In the latter case, the aryl halide of formula (XIX) is first reacted with 1-octine of formula (XXX) and then hydrogenation of the resulting (XsXXX) alkyne derivative yields the nitrogen-protected fumaric acid derivative of formula (XVIXX). Deprotection is carried out as described above to give (fing) fmodol.

F-1419 New 2015.05.23

F15QOQ23

J.V

Zi-H jgCg '

R1 .b

Reaction equation 16: Preparation of Fingollmod from aryl halide g of formula (tIX)

In order to provide an octyl substituent at the 1-position instead of the halogen, a. Organic Zinc Compounds of the Negishi Reaction Formula (LX)

- in which

H is XnX or ZnX.UY in which

X and Y may be the same or different and are chlorine, _bróm--,: iodine.

The reaction is catalyzed by salts and complexes of transition metals, particularly palladium and nickel, optionally in the presence of ligands. Preferably, these two! ^Oe? Phosphines of the formula R ^S and F {OR ^t; ) (Other (Oldd general formulas of the Oldd general formula, heterocyclic carbene ligands, and tri-toothed (so-called p> inoer) li.gandum.) On amines and phosphines - in which

R ^B , R ^{? and} R is an optionally sznbsztitüálf ~ alkyl, cycloalkyl, biclklnsos or aromatic or heteroaromatic group, and particularly preferred that R MAIN an RO, when R * is optionally szubsztiteáit bifeni1 group,

Other additives further influence the direction of the reaction. Examples of slides include li.X and ZbX ₂ - where X is chlorine,

P-1419 "new enamel

FIS00023 or iodine and planes and dienes, or tertiary and heterocyclic amines.

In another preferred embodiment, the (LIX) aryl halide reaction of 1-oktinnal íIXI) wherein catalyzed by transition metals or salts and complexes, particularly palladium and copper or both of: a time, the above ligand derivatives are ali alkslmazzuk tent as küIonosén PR * R ^y R ^s deprives Inoki, wherein B * # = R '- ^R E, where R ⁶ is an optionally substituted biphenyl group, '10 The reaction may be polar or non-polar, aprotic and protic solvents in presence of base like alkali carbonates or amines,

The best results are obtained with the latter biphenyl ligands, preferably in the presence of XPhos, 8d ° or ^: Pd ²⁺ complexes (PdideCh) ₂ Cl ₂ , Pd ₂ (dba) 1) or preferably directly in the presence of a palladium / carbon catalyst in which ^LIX;) falling within the formula aryl chloride (Pl - ^R2 ~ Ma, B ³ - Sec, 21 ^=: = chloro) may be used, (LVI) aziridine of formula regioselective Grignard reactants of the formula used bag (LVXX) íelnyi20 easily can be prepared by reaction of the corresponding benzyl halogeols with excess magnesium metal.

benzyl halides containing chloro, bromo or iodo at position 5 are readily available commercially.

The starting material of our 4-oct-1-benzyl-1-ha 1 ogenide is 4-chloro-beη z oe s av-me t i 1 es z z e r, ars 1 ybö 1 4 - o kt i 1-in z oes a. The reaction mixture is obtained by reaction of octyl magnesium chloride or octyl magnesium bromide in the presence of an iron salt catalyst. While optimizing the special reaction on the taste, the amount of solvent used was significantly reduced to make it more suitable for industrial use, yielding 4 ™ octylbenzyl alcohols with good yields of Synhydride or X&R reagent to reduce ethyl octylbenzoic acid methyl ester. 4-Octylbenzyl alcohol is converted to α-octylbenzyl chloride by thionyl chloride according to the known procedure. Similarly, 4-octylbenzyl-sulfol is converted to 4-octylbenzyl bromide with phosphorus tribromide.

R-1419 “New ^{, f} 3/2/2015

R1500023

During the production of Grlg nard ski, Ganz11-haloyesidekfedi is also an important source of solvent precipitation for the priming of the primary.eril moles and for achieving a high conversion rate. The main player}. agg most ere tton going on - yo yee ye ye, i wo ... rosti ίο e re le r «bo k11 - ether, 2 -mo t .11 --te P. r ah 10 roforà ve re re hydro furans. ···· Griégard reegée solution with herbaceous oak, aroma charcoal rogers, preferably toluene, is produced by the following formula (year formula echiridine reg 1 oste 1 ekk 1 v re 1 ny 1, fig. eat nasaunezs .sruea for many 15 signs11,

The general formula of this is 1 r roi n-starch, stone rtg heat goule the lene fide procedures described in eternal or trench analogue skin file ok Ok, O out start1 XXWXX image trl.s - '' jhydrorimethyl e-rlno ancestor the ni trogen atoákau supplied with old veddesenor, .may the blue Pld case i. The group r is traced in the aesthetic or blue form to the superficial form} and the radishes are scattered as active, cooked or other benzene-containing semen, paté patti, preferably soda ash-thi? repository corresponds to 1 ₁ 7-drexa-l-azasplro (z. tj oka; '· their atoms, their chalices, thus, whatsoever.iitgdk g oeidákduu bVXn (heat - heat, shoot go cl and kkib main e> p - Mg , the heat of the formula Cd trees amid the starch mechatine, which is the same as the tree of your fingers,

a LVIb

P-1410

20! ? THE! 50th

Nusi

R15GGÖ23

22nd

Examples

Starting Materials (Examples 1 ~ 14)

- o k t í 1 ~ be n z o ss a v -sast 11 s s z tér '

A solution of octylmagnesium chloride (70 mmol) in tetrahydrofuran (THF) (35 mL, 2 d) was added dropwise to a solution of 10 g (58.6 mm) of methyl chlorobenzoic acid in methylene carbonate (Felaeaebd) (90 mL). dry TH.F and 10 mL of b ™ methyl-2-pyrrolidone. (NMP) under argon, with stirring over 1 hour, and the mixture. and stirred at room temperature for an additional 1 hour. The mixture was poured into 99 ml of water, 10 ml of concentrated hydrochloric acid and 200 ml of diethyl ether, shaken, the phases were separated and the aqueous phase was further extracted with 2 x 100 ml of diethyl ether. The combined organic extracts were washed twice with water and magnesium sulfate. dried. The product obtained by distillation of the crude product was 11.7 g (80%) of an oily liquid (HALC content 99.7%), b.p. 120-122 ° C / 11.99 Pa (0.09 bp).

In 4-oct11, a solution of zeolic acid methyl octylsmonium chloride in 35 ml, 70 mmol of diethyl ether was added dropwise to a solution of 10 g, 58.6 mmol of methyl chlorobenzoic acid and 1 g of ferric acetyl 25 acetonate in facacac). 90 mL of dry THF and 10 mL of NMP with stirring under argon for 1 hour.

After the addition of 1 ml, an additional solution of 0.3 g FeAcacB is added in 3 ml N0P with another dispenser so that the addition of the two components is completed at the same time. The mixture was stirred at room temperature for an additional hour and then poured into a mixture of 90 ml of skeleton, 10 ml of concentrated hydrochloric acid and 200 ml of diethyl ether. The mixture is shaken, the phases are separated and the aqueous phase is further extracted with 2 x 50 ml of diethyl ether. The combined organic extracts were washed with 2 x 100 mL water and dried over magnesium sulfate.

91500 023

13.6 g (93%) of an oily liquid were obtained, HPLC content 99.3%, boiling point 118 - 122 ° C / 10.68 - 11.99 Pa (0.08 - 0.09 boiling point).

In δ 4-octyl, zi1-alcohol% sodium torso (2-methoxyethoxy) aluminum hydride (Synhydride) solution was added dropwise over a period of 1 hour, 2.4.8 g of methyl-ethyl-benzoic acid methyl ester prepared in 200 ml of toluene. , stirred in a nitrogen atmosphere

Stir at 2-5 ° C and overnight at room temperature. It's your mixture! Dissolve by adding 150 g of sodium potassium tartrate solution in 300 ml of water - be careful not to foam strongly at the beginning. The aqueous phase was extracted with 4 x 50 mL of toluene, and the combined organic layers were washed twice. It is washed with 50 ml of brine and dried over magnesium sulfate. Concentration gave 18.4 g (83 evaporation residues (96.5% HPLC)) which were used in the next reaction without further purification.

In 4-oct11, a solution of 1 M-lithium aluminum hydride in THF (1 mL) was added dropwise over a period of 1 hour with 2.5 g of 10 mmol of methyl 4-octylbenzoic acid in 50 mL of THF solution of nitrogen was stirred at 2-5 ° C under nitrogen and the mixture was stirred at room temperature overnight. We'll demolish the one. 15 mi. water and 15 ml of a 15% sodium hydroxide solution and 45 ml of water were added gradually. The resulting mixture was stirred at room temperature for 3 minutes, the insoluble material was filtered off with suction and

Wash with 5 mL ethyl acetate. The aqueous portion was extracted with 4 x 25 mL of ethyl acetate, washed extensively with brine, and dried over magnesium sulfate. Evaporation gave 2.1 g (95%) of a residue, HPLC content 98.9 L, which was used in the next reaction without further purification.

P-1419

P15OH023N-octylbenzyl chloride

Thiourea chloride (6.5 ml) was added to a stirred solution of 14.2 g (64 mmol) of 4-octyl5-hemilyl alcohol in 350 ml of acetonitrile and the mixture was stirred in a 9 ° C bath for 1 hour. After cooling, the mixture was treated with 700 mL of diethyl ether. diluted, washed with brine (4 x 10 mL) and water (2 x 100 mL). After drying over magnesium sulfate, the residue was distilled in vacuo to give 12.5 g, <81% of product 4, b.p. 110-115 ° C / 23.79 Pa. 0.18 boiling).

-i ti i in zi 1 -b romi d

Phosphorus tribromide (25 mL) was added dropwise over 1 hour to a stirred solution of 14.2 g (64 mmol) of 4-ethylbutyl alcohol in 40 mL of diethyl ether and the mixture was stirred in a bath at 70 ° C for 1 hour. After cooling, the mixture was diluted with diethyl ether (700 mL), washed with brine (4 x 100 mL) and water (2 x 100 mL). After drying over magnesium sulfate, the residue was distilled in vacuo to give 14.3 g (77%) of product, b.p. 132 DEG-141 DEG C. (72 DEG-99 DEG-106 DEG).

{5-tert-Butyloxyl-carbonyl-1-amino-2,2-dimethyl- [1,3,4] dioxan-5-yl] -methanol. · XX2CVX1la;

120 g (0.55 mole of di-tert-butyl difcarborate (BoCgO) were added with stirring at room temperature to 60.6 g, 0.5 mole of tris-hydroxymethyl-1-aminomethane (? XXVXX) in 4 50 ml of dimethylformamide ( DMF) and stirred at room temperature for an additional 2 hours, add 74 ml (0.6 mol) of 2,2-dimethoxypropane and 4.8 g (25 mmol) of p-toluenesulfonic acid monohydrate and stir the homogeneous reaction mixture for 18 hours at room temperature. The organic layer was dried (Na 2 SO 4) and evaporated to give 135 g of crude product, which was treated with hexane-methyl ether. Crystallization from tertiary butyl ether (ITHEI 9: 1). Together with the fraction obtained after concentration of the mother liquor, the total amount of 3 x XXVIXXa was 115.6 g, 88 l colorless, needle

in crystalline form, m.p. 99 to ^c 'C. ^l H : 1R (2nd MHz, CDCl3; § - 1.43 (s, 3H), 1.46 (2x s, 12R), 3.73 (d, 2H, - 6.5 Hz), 3.80 (m, 2H), 3.86 (m, 2H), 4.18 (bs, 1H), 5:31 10 (bs, 1H); ^I3 C NMR (62.5 MHz, CDCl3); 5 - 20:38; 26.72; 26, 31

(3C); 53.65; 64.38; 64.69; 80.43; 98.7 δ; 156.41.

5-tertiary-Bioxyloxycarbonylamino-1,2-dimethyl- [1,3] dioxox-515-yl} methyl-1-methanesulfone &lt; / RTI &gt; KXiXaa}

Methsulfonylchloride (2.55 mL, 33 mmol) was slowly added dropwise to JCSXVXXXa (7.84 g, 30 rol) and trlecylamine (10.5 mL, 75 mmol) in 60 mL. dichloromethane solution at -5 ° C, while the temperature in the pre-effluent is raised to 3 ° C. The reaction mixture was slowly warmed to room temperature and after 3 hours poured into 150 mL of B1E and successively 2x. Extract with 50 ml of water, 2 x 50 ml of an aqueous solution of 10-citric acid and 50 ml of a saturated sodium bicarbonate solution. The organic phase is dried over sodium sulfate and after evaporation, 9.73 g,

96% of the mesylate XXXXIaa is obtained as a pale yellow crystalline form. For analytical use, the product was recrystallized from MTBB; the obtained crystals had a melting point of 97-99 C. 1131 ^Ö (250 MHz, CDCib: § - 1:41 is 3.h), 1:44 (s, 9H), 1:46 (s, 3H), 3: .04 (s, 2 Hh , 3.85 (d, 2H, d - 12.0 Hz),

3.99 Cd, 2.H, J = 12.0 Hz), 4.58 (s, 2H), 4.77 (bs, 1H). ⁱ³ C KMR (62.5 MHz, CDClsB § «22:19; 24.60; 28.20 (3C), 36.93 51.36;? 62.79, 62.34 (2C); 68.38; 98.39;. 154.57 HRbS (APCI-MS, posltive mode); cálculaied for cy ' 7 340, 142449 Oa, fnn d; 340.14 25 »

P-1419

P1500023 &lt; tb &gt;&lt; tb &gt;&lt; tb &gt; loxyloxycarbonyl &lt; / RTI & gt ^; - ^: 2,2-dimethyl, 3) dioxa-5 ~ 1) mefc 1 -ps.ra-1 to 1-ululone t (& XX I VAT)

Para-toluenesulfonyl chloride (2.0 g, 10.5 mmol) was added (2.6 g, 10% w / v XXWIIZa) and trimethylamine (1.5 ml, 10.5 mmol) in dichloromethane (20 ml). 120 mg of 4-methylethyl-ainoino pyridine (IOMAB) are added and the mixture is stirred at room temperature for 4 hours. Subsequently, 15 ml of saturated ammonium chloride solution and 5 ml of water were added, the organic layer was separated and the aqueous layer was extracted with dichloromethane (2 x 10 ml). The combined organic fractions were washed with aqueous 10 L citric acid and saturated sodium bicarbonate solution. The organic fraction was dried over sodium sulfate and the product obtained after para-be 15 was dissolved in hexane-ell-setafc (StQAc) 1: 1; the solution was filtered through a 50 g silica gel column and washed with 500 ml of the former solvent mixture. Evaporate and crystallize from MTBE to give 2.6 g of 62% OXXXab tosylate, m.p. 106-107 ° C. 'R RAS (250

MHz, CDCl3: 3-1.40 is, 6H), 1.42 is, 3R), 1.43 (s, 3H), 2.44 is, 3H), 3.76 id, 2H, J is 12.0 Hz), 3.63 (d, 2H, J = 12.0 Hz), 4.34 (s, 2H), 7.33-7.38 (R, 2H), 7.77-7.31 (2H). ⁿ CWR 162.5 MHz, CDCl 3): δ = 21.54; 22:07; 24.59; 23.17 f3 €); 51.37; 62.68 (2C); 63.11; 68.66; 98.71; 127.95 (2C); 129.86 f2Cj;

132.41; 144.94; 1:54:41. BRMS (APCI-MS, positive mods): calculated for C _(g H _{S 1} ) NO ₇ S (MH + 416.173749 Da, found 416.1742).

1- (tert-butoxycarbonyl-6,6-methyl-11,5,7-dioxa-130 azaspirool) thoctane (R * = R ² - Ma, R ³ - BOG)

P-1419

B1500023

you

A solution of sodium hexamethyl-1-disilazane (SlaHMDS) (17 mmol) in 2M THF (17 mL) was added dropwise to a solution of 9.72 g (28.64 mmol) of mesylate in 150 mL dry THF cooled to -6 ° C over 5 min. while the temperature of the resection mixture rises to -2 ° C. Over 2 hours and allowed to warm to room temperature and gradually added to 150 ml of saturated ammonia solution chlorite, 50 ml water and ^150: mL MTBE. The aqueous phase was separated and extracted with MTBE (2 x 50 mL). The combined organic fractions were washed with an aqueous solution of 10% citric acid (1 x 50 mL) and saturated sodium bicarbonate solution (1 x 50 mL). After evaporation, the light beige crystalline material was aziridine (8.8 g,% LVIa). Crystallization from hexane gave a sample with a melting point of 49-52 ° C, te NME (250 MHz, CDCl 3); Δ = 1.4 δ (s, 3H), 1.47 (s, 9H), 1.52 (s, 3H), 2.21 (d, 2H, J = 0.7 Hz), 3.65 (m, 2K, δ 12.8 Hz), 3.97 (m, 2H, t-12.6 Hz). te: NME (62.5 MHz, CDCl ₃ ): δ - 22.69? 24.73; 27.95 (3C); 35.50? 40.24; 63.94 (2C); «1.74; 98.69; 166.37. HEMS (APCI-MS, Gestivé Moee): Calculated Forums: 204 Judgment: 244.154335 Da, Source: 244.1543.

Example 11

1- (tert-butoxycarbonyl) -6,6-dimethyl-7,7-dioxa-1-azaspiro (2.5) octane (X, VXa, te-te-te, te-BOG)

HaBMDS 1.2 mmol, 0.6 mL of 2 M in THF was added slowly, eseppenként 0 ^Q C ~ rs frozen 416 mg, 1 mmol púratoiuol sulfonate formula LXIlIab allowed to warm to 10 ml of dry THF was added and stirred at room temperature. After 4 hours, 50 mL of saturated ammonium chloride solution and 2 mL of water were added gradually and the mixture was extracted with 3 x 5 mL of ethyl acetate. Dry over anhydrous P-1419 P1500023 sodium sulfate and evaporate to give 226 mg, 93% &lt; RTI ID = 0.0 &gt;&lt; / RTI &gt;

Be n z i .1 1,3 - slides d r o x i - 2 - {h i d r oxym e t i .1} p ropa n - 2 - 1 i ka rbamate

While stirring at room temperature for 1 h, 14.5 mL, 100; Benzyl ester of chloroformate was added dropwise via a linear addition of 12.1 g (1.5 mmol) of tris (hydroxymethyl) aminomethane (XOYXX) and 10.6 g (125 mmol) of sodium bicarbonate in 50 ml of water and 100 ml of ethyl acetate. The mixture was diluted with ethyl acetate (100 mL) and washed with water (2.times.50 mL), the organic phase was evaporated to dryness and toluene (50 mL) was added and the mixture was repeated twice. 1 g, 71%, which was used in the next reaction without further purification.

(S-Benzyloxycarbonyl-amino-B, 2-dimethyl-1,3] dioxane-52,11'-methanol-OTYXXXb)

5.1 g (20 mmol) of benzyl 1,3-dihydroxy-2- (hydroxymethyl) propan-2-yl carbanate; 3.0 g (28 mmol) of 2,2-dimethoxypropane? A mixture of toluenesulfonic acid monohydrate and 15 ml of DMF was stirred at room temperature for 10 days, diluted with 50 ml of diethyl ether and extracted with 3 x 10 ml of saturated sodium bicarbonate solution and 10 ml of brine. g of crude product of formula 3 £ XVXXXb is used in the following reaction.

.1 - í ben z i luxi - ka rbon 11; ··· €, 6-Dimethyl-5,7-d 1 oxa -1axaspiro [2. In Branches (1-VXb (νV - il = - = Me, R '' - BzQCO)

F-14I2

FI 500023

X.

c

'0

Example 11: The procedure described was 83% aziridine (LVI-head), HPLC purity 95-97%.

PROCEDURE OF THE INVENTION:

Example 15 »

- i t ereler- but i 1 óxí - ka r bem 11- ami. no} - 2,2 - dichloromethane 1-5 - (4-10 k111 phenethyl) -1,3-dioxoxan (terelerenethyl 2,2-dimethyl-o- (4-ophthylphenethyl) -1 , S-dioxo-S-yl-carfoamate) (spawn)

A) 4 ml of magnesium sulfate, coated with 2 ml of dry diethyl ether, was activated with 25 µl of 1,2: diphosphoethane in a nitrogen atmosphere. At the end of the reaction, a solution of 0.4 g of 4-methylbenzyl chloride in 2 ml of dry diethyl ether is added at one time. The reaction was continued by the gradual addition of 2.0 g of a solution of 4-octylbenzyl feloride in 8 ml of dry diethyl ether and 5 ml of telned solution. The mixture was then stirred at room temperature under nitrogen for 1 hour. Using the obtained (subject ΑΥΧΧ'Ί formula Grlgnard salt (in the formula 27 and X ¹ are as given core) solution was sucked into a syringe and B) was performed ..

B) The Grlgnard salt solution obtained in Step A is added dropwise to a stirred suspension of 1.2 g, 5 mmol of aziridine (5 mmol) and 0.5 g of CuSr-MesS in 0.5 mL of 25 mL of dry diethyl ether. ® at 1 hour. Thereafter, the mixture was stirred at the above temperature for 1 hour and then stirred overnight in a nitrogen atmosphere without cooling. The mixture was quenched by addition of 7 mL of saturated ammonium chloride solution. The insoluble fraction was filtered through silica gel and washed with diethyl ether. The filtrate was separated; the aqueous layer was extracted with 2 x 5 mL of diethyl ether. The combined organic fractions were washed with brine (2 x 3 mL) and dried over magnesium sulfate. The residue was concentrated in a Kugelrohr distillate (0.067 Pa).

P-1419 _; "Night 50.09.09.23

Distillation under vacuum (P590023) in vacuo afforded 0.65 g (yield 72% (calculated as LVXa) r.a.) of a solid, HPLC purity 93.5%.

The sample pentane Crystallization of colorless crystals M.PIíC purity 97.6%, melting point 61-65 ^Ö 'C.

5- (tert-butyloxycarbonylamino) -2,2-dimethyl-5- (4-octylphenethyl-1,3-dioxoxane (tert-butyl 2,2'-dimethyl-S- (4- octyl ~ f en eti 1) -1,3 - dl oxane - 5 - i1 - ka brown (LVX XX a)

In the procedure described in Example 15, 83% of the product (bVXXXa) is obtained using 2-methyltetrahydrofuran.

5- (tert-butyl-phenyloxycarbonyl-3-yl) -5- (2- (4-chlorophenyl) -ethyl) -2,2-dimethyl- (1,3) -disane (bXXa, R ¹ -R ² - Me, 3) ? - Bog, $ ⁴¹ ~ chlorine)

A) 3.2 g, 132 mmol of magnesium were coated with 25 ml of dry diethyl ether layer at ISO p.s. Activated with 1.5 mol of 1,2-potassium ethane in nitrogen gas atmosphere, after completion of the reaction

The mixture was bound to 15 ° C and a solution of 10.6 g (65 mmol) of para-chlorobenzyl chloride in 110 ml of dry diethyl ether was added per hour, while the slurry was cooled to 15-25 ° C. After addition of all the chlorides, the mixture is stirred at room temperature under nitrogen for a further 30 minutes. The Grignard saline solution is aspirated into a syringe and used in step 3)

3) The Grignard ab solution obtained in Step A) is added dropwise to a stirred suspension of 4.9a, 20 mmol of LVXa in syrup and 2.5 g of 12 mmol of CuBrene in 30 mL of dry diethyl ether at -65 ° C. that the temperature does not rise above -60 ° C. After dosing is complete. the mixture was allowed to slowly warm to ~ 10 Ü L (15 h) and quenched with 60 mL of saturated ammonium chloride solution and 20 mL of water. The organic layer was separated and the aqueous layer was extracted with 2 x 25 mL of TBE.

The combined organic fractions were washed with 50 mL of brine,

3-1419 91500023 'Filtered on new silica gel 23.09.2015 and evaporated. 4 ml of 5 volumes of heptane containing 5 volumes of MRE are added to the oily distillate residue, the mixture is placed at 30 ° C and after ca. 20 mg of product, inoculate at 5 ° C for a few hours. The procedure, 5.9 g, 79% purity, yields a colorless needle-like crystalline Formula XXXa, m.p. 94-95 ° C. Similarly, 0.9 g of product is obtained from the mother sky. Thus, the total yield of the compound of formula (XIXa) is 6.8 g, 92%.

1 H NMR (250 MHz, CDCl ₃ ): δ - 1.41 (s, 3.Hj, 1.43 <s, 3H), 1.47 10 (s, 3H), 1.95 (m, 2H), 2.54 (m, 2H), 3.67 (d, 2b, «7-11.7

Hz), 3.88 (d, 2H, J = 11.7 Hz), 4. (Fes, 1H), 7.07-7.14 (m,

2Ή), 7.18–7.27 (m, 2.H). ¹³ C AMR (62.5 MHz, CDCld: 6 - 19.80; 27.33; 28.42 (3C); 28.51; 33.52; 51.68; 66.35 (2C); 79.46; 98.43; 128.51 (2C); 129.71 (2C); 131.65; 140.45; 154.90 .MS (AFC1-MS, positive mode: calculated for Ci ^ H ^ NO ^ CX 370.1780 Da, fonno: 370.1788 Da.

. example.

5- (tertiary-butyl-oxycarbonyl-amino) -5- (2- (i-chlorophenyl) -ethyl) -2,2-dimethyl-1,3,3-dioxoxane (11Xaj, (R ¹ -R ² -He, .R ³ -) Boc, R ⁴³ chlorine)

Following the procedure described in Example 17, using CuSr-Me ₂ S in 15 molar copper iodide (Cul), 88% of the product of formula LXXa> were obtained.

Example 19

5- {tarcíer-bntiloxi-butoxycarbonylamino) -5- (2- (4-Chlorophenyl) efII] 2,2-dimethyl- [1,3} dioxan (LXXa), (Fb - R ^Z = Me, ^R3 - Boo, H ^i; chlorine)

According to the procedure described in Example 17, using 20 moles of copper chloride (CuCl) instead of CuSleil, S was chromatographed on 2 mmol (εV $> of siridine on silica gel (2 10% ethyl acetate / n-hexene) 69%. (LXX &).

A15QGÖ23

A-1419

Adjusted on 5/23/2015

Example 20

5- (tertiary-phenyloxy-cartiloylaminyl) -5- [2- (4-chlorophenyl); ethyl 2,2-dimethyl: L, 3, 3j-dioxane (XIXa, (R ¹ Fdd, R ³ Boc, R ¹ chloro;

According to the procedure described in Example 17, using 5 rolls of dilithium tetracl.orökproprotein (HizCuCl and a 1: 2 mixture of solvent tetrabridialurane-difcyl ether (THF-Etyd), 2 nmei; LVIab) aziridine instead of CuBr · Μβ · _2: § silica gel chromatography (2-10% ethyl acetate / n-hesane) 34%

The product LXXa is obtained,

5- <feeroier-butyloxy carbonyl ami.noj -5- [2- <4 tromfenil) ethyl} 2,2-dimethylaniline [1131 d: ioxán (XXXb), (R 7 = R ~ ³ He, R. ^J ~ Boc, R ⁴ⁱ 15 bröm)

A) A solution of 0.5 Mp-bromobenzyl magnesium bromide in diethyl ether was prepared from 1.5 g of 60 mmol of magnesium and 7.5 g of 30 rmole of p-brbm-benzyl bromide in the procedure described in Example 17.

B) According to the procedure of Example 17, 3.1 g of 74% pure bramide of formula LXXfo are obtained in 2.43 g, 10 mmol of aziridine of formula XVXa, 1.23 a, 0 omol of GuSrl4e ₂ S and 30 mmol of above. The product is crystallized from an image gallery of 5 volumes of MlBE using Grignard reagent solution.

in crystalline form, m.p. 34-87 ° C.

Oil RMR (25 0s, CDCl2; h - 1.42 (s, 3H) , 1.43 (S, 3H), 1.47 (s, 9H) , 1.35 (m, 2H), 2.52 (m, 2H1, 3.67 (d, 2H, d === 11.6 Hz), 3, 88 (d, 2K, , 7: * 11 & Hz), 4.97 (bs, 1H ···, 7.02–7.11 (m, 2H), 7, 33-7.42 (m 2 H) . ^X3 C 117: (62.5 MHz, CDCl3: δ - 19.64; 27.33; 2: 8.34 (3C) ; 28.49; 33.33; 51.56; 6 6.26 (2C); 73.35;

38.36; 119.57; 130.36 (2C); 131.33; 2C); 140.88; 154.83. HRMS (AFC1-HS, positive motive); oalcuiated fór Cl 11-1117 ³ 7r fWHl ⁺ : 414.1274 Da, found; 414.1280 Da,

81500023

8-1419

Wrá gá.lt 2Ö15 »03. 23

Example 22.

5-berthieryl "Byloxy" carbonyl "amino} -5- [2- (4-bromophemyl) ethyl] 2,2-dimethyl (1,3) -dioxane. (: &Lt; 3 &gt;), (R ¹ - R ² , R ³ ~ Boo, βΛ ^: == brőml

A) According to the procedure described in Example 17, 0.5 M p-bromobenzylmagnesium magnesium btomide in 2-methyltetrahydrofuran was prepared from 1.3 g of 70 µM magnesium and 9.0 g, 36 mmol of p-bromobenzyl. -bromldból.

By the procedure of Example 17, 2.06 g, 69% of pure 10 ts (AlXb) bromide are obtained from 2.43 g, 10 mmol (LVXa) of aziridine, 1.23 g, 6 mmol of CuBr0SegS and 30 mmol of the Grignard reagent prepared above. the product is crystallized from bsptene containing 5 volumes of MTBR,

23 <example

5- (tertiary-butyloxycarbonyl-3-yl) -S- [2- (i-bromophenyl) -ethyl] -2,2-dimethyl- [1,3] -dioxane (MW, (R ⁵ - R ² - into, R ³⁾⁾ - Bot, R ⁴¹ chrome}

A) According to the procedure described in Example 17, a 0.5 M solution of 20-p-bromobenzylmagnesium bromide was prepared in strain-MIBE 1: 2 • in a mixture of 733 mg, 30 mmol of magnesium and 3.75 g, 1.5 mmol. p-bromo-benzyl-bromldből,

By the procedure described in Example 17, 2 mmol of the formula (Wla) were chromatographed on silica gel using aziradio and 6 mmol of Grignard re.25 agent solution prepared above. (2-10 L of ethyl acetate / n-butane), 71% (X, XXb) of the product ka30 5-tertiary-butyloxycarbonyl-aminoHo-4-bromophenyl) ethyl] 2,2-dimethyl [1, 3] -dioxane (LXXb), (R ~ ~ R ² == He, R ³ ~ ·. Boo, R '' ~ br)

According to the procedure described in Example 17, a 0.5 M solution of p-bromobenzyl magnesium bromide in toluene / diethyl ether was prepared.

P-1419

Kprri Gel t ”9/2/2015 3

FI 500023, a.In a mixture of 7 30 rags, 30 mmol of magnesium and 3.75 g of 15 ramol of p-bromobenzyl bromide.

3} 17, according to the procedure described in Example 2, 2 dm cd. (LVZa) Chromatography of aziridine and a solution of Grignard re6 agent (6 moles) above on silica gel (2-10% ethyl acetate / n-hexane) gave 90 5 (XX3Ss) of ka10 5 - (tertiary-butyloxycarbonyl). amino> -5- (2- (4-Bremenylmethyl) -2,2-dimethyl-3] -dioxane fLXMb), Phaden «H ² Me, R ³ » · Bee, R ⁴ⁱ «= Fur)

According to the procedure of Example 22, using 2: 0 mole of copper chloride (Cu: Gl) instead of CuBr-bOjS, 2 mmol of aziridine LVXa (45 mmol) was chromatographed on silica gel (2 - 10% diethyl acetate / n-hexane 53%). The product of formula LOb) is obtained.

5- (tert-butyloxycarbonylamino) -5- (2-14- (1-octin-120-yl) phenyl] ethyl] -2,2-diretyl [1,3] -dloxane (: mi), ( R ¹ - R ² - Fri,

^:::: r ^a Bee] ml of dry dimethylacetamide and 1-octyne 550 ui (Χ.ΧΣ) was added to 555 rag, 1.5 raraol (.XIXa) fcloridot formula aryl; 311 rag, 2.2: 5 rarify potassium carbonate? 14 rags, 2 moles of X2b.es-1 and IQ:%, 32 mg of 2 mol / d / C catalyst in degassed and argon gas filled lorabix. The reaction mixture was heated in an oil bath at '110 ^° C for 24 hours. The mixture was brought to room temperature and 5 mL MTBE and 5 mL. Dilute with n-hexane, filter through silica gel and wash with 1 x 5 mL of 10% nitric acid solution, 1 x 5 mL of saturated sodium bicarbonate solution and 1 x 5 mL of salt. The mixture was evaporated and separated on silica gel by column chromatography (2% ethyl acetate / n-hexane). 351 rag, 53:% pure sXkin (ΧΧεχ) is obtained which is a pale yellow crystalline solid.

2150002 3

P-1419

Corrected 2315.09.23

5-tert-butyloxycarbonylamino} -5- [2- [4- (1-octin-11-yl] above] ethyl} -2,2-dimethyl-1,3] dioxane? R ^; 'main - Me,

R ⁵ - Boc)

Example 26 wherein 1 mol

Bubid was used instead of lo% _: d / C to give 34% £ XXX.

5- (teroier-butyloxycarbonyl-amino} -5- [2- (4- (l ~ l ~ oct-

11} fan! jetyl I -2,2-dimethyl ± 111,33-dioxane (LXXX>, (major ~ R ² = Me,

R ³ - Soc)

Following the procedure of Example 26, but using arylforomido (IIIXZb) instead of chloride (XiXXa), 27%} LX2J are obtained.

Example 29

5- (tert-butyl-carbonyl-carbonylamino) -5-02- (4-octylphenyl) -ethyl] -2,2-dimethyl- (1,3) -dloxane (CLVXXXa), {N - R ² === Me, R ³ - Bee }

116 mg, 0.4 mmol of aryl bromide of formula X 2 X 2 S 5>, 6.5 mg, 4 molar SBhos reagent and 1.8 mg, 2 molar palladium acetate (? D (OAc) ₂ ) are dissolved in 2 ml of dry THF. in a Schienk degassed flask. A solution of 0.5 A of n-octyl zinc bromide; n-CsH; 72n 3r} in 1.2 mL of THF-Pen was added via a linear feeder at room temperature for 30 minutes. After 30 rounds, the reaction mixture was quenched with 4 mL of 0.5 b ethylene diamine tetraacetate trisodium salt (NasEBTA) in water and extracted with 3 x 4 mL of 2: 1 MT3E. after the crude mixture was purified by silica gel chromatography (2-10 s with an ethyl acetate / n-hexane), 113 mg, 63%. pure colorless crystalline CLVXXXa) of the formula of melting point 63-65 C. ^P

5-tert-butyl-oxy-carbophenylamino} -5- [2- (4-octyl) -enyl] -ethyl] -2,2-dimethyl- [1,3] -dioxane {LVXXXa}, (PE = PE = he, R @ ³ ~) sec)

F-1413 P1500023

Corrected '23.03.2015

148 mg, 0.4 mmol of aryl chloride (LXXa), 7.5 mg, 1 mol% of RuRhos reagent and 1.8 mg, 2 molar palladium acetate in fFd (OAc) j) are dissolved in 2 ml. dry THF in a Schienk degassed flask. The mixture was heated in a bath to 60 ° C and thereto. at 90 ° C, a solution of 1.8 ml of 0.5 M noctyl zinc bromide in THF is added over 90 minutes. Reaction mixture A was heated at this temperature for a further 2 minutes, cooled to room temperature and worked up according to the procedure of Example 20 to give 03 mg, 52% of pure volume (LVXXXa),

5-tert-butyloxycarboxylic amine) -5- (2- (i-octylphenyl) ethyl] 2,2-dimethyl-1/3] -dioxane iLVXXXa), (2 '- R ² - Me, ti - Roo) )

A) According to a method known in the literature, Q, 67

M solution of n-octyl bromide and zinc h; ~ C _s R ZnBr) in dimethyl acetamide (DíAcl was 0.08 g, 15 mmol oinkporból 1.03 g, 10 mmol of n-1 ο oktilbrom idb tR ibid? S,: Org. Lett .0303,5,423 ;,

B) 332 mg, 0.8 mmol of aryl 1-bromide of formula LXXfe, 1.3 mg,

2 µl of 4 mol% SPhos reagent and 3.6 mg of 2 molar palladium acetate (PdíCAch) were dissolved in 4 ml of dry THF in a Schienk-type degassed flask! k.ban. 1.8 ml, 1.2 mmol of the above octylidene bromide (n-CsHi;? ZhSr>) solution are added dropwise over 30 minutes at room temperature. After a further 30 minutes, the reaction mixture is worked up according to the procedure described in Example 20. 61 mg (61%) of the pure product (LVXXXa) are obtained.

5-tertiary-butyloxycarbonylamino) -5- [2- (4-octylphenyl) ethyl] -2,2-dimethyl-3] -dioxane (LVXZXa), R ¹ -F ² - Me, R ³ - Boc)

166 mg, 0.4 mmol of aryl 1-bromide LXXb. and 4 mg, 2 x 0.1% bis (tertiary-butylphosphine) palladium (Rd-t-BurR) _s ) was dissolved in 0.5 ml of dry TRF and 1.5 ml of NMR in a Schienk degassed flask. Cool to 0 ° C and add a solution of 0.3 M n-octyl zinc chromide (n-ChKnZnSr; 1.2 mL in THF and reP-1410).

Corroded 2Ö2.03 <23

The action mixture P1500023 was stirred at room temperature for 1.5 hours. Following the procedure of Example 29, 65 mg (36%) of the product (LVZXXa) were obtained.

Example 33

5- (tert-Butyl-cyanophenyl) -amino- -5- [2- (4-octylphenyl) -ethyl ™

2,2-dimethyl (1,3t-dioxane (LYXXIa), (R ³ - R ² === Me, R ³ - Bot)

A solution of 166 mg, 0.4 mmol of aryl bromide IIIXXb and 5.5 mg of PBBPSI-IPr catalyst in 2 ml of dry NhP-bsn

1Θ Schlenk-type flask was degassed by esi .. At room temperature, added to 0.5d n-octyl bromide oink <heated n ~ C _& H? Rj-2'hB ÍRFes 1.3 ml of the reaction solution and 40 ^c C. After 4 hours, it was processed according to the procedure of Example 29. 52 mg (29%) of pure product (XtVXXXa) are obtained.

- (tertiary er-b ut i oxy - ka r bon 1 1 - amino) - 5 - [2- (4-octyl) fer, ethyl; ~ 2, z-dimethyl [1,3] dioxane (WXXXa), (R ¹ - R ² - Me, R ³ · «Boc)

The procedure of Example 33 was modified and 3.3 lithium bromide (LiBr) (3.3 ml) was added to the reaction mixture, a pure product of formula XIXIXa}. is obtained., its production1 41 1.

5- (tertiary-butyloxycarbonylamino) -5- [2- (4-octiphenyl) ethyl] -2,2-dimethyl-1,3-dichloro (LVXXX &amp;), R @ ¹ = R ² = de, R ³ - Boc)

A 34,. Using the aryl chlorine of formula XXXa in Example 1, instead of the bromide of XXXXa, 22% of the pure product XIXXXXa are obtained.

P-1419

Adjusted 23/09/2015

Pl500023

Claims (5)

Patent Claims A process for preparing X-amino-2 - [[2-yl-octylphenyl) -ethyl] -propane X 3 -diol. characterized by the opening of rings on the collar of the intermediate of formula hVl) _R x ^R X % ... / |> -R ³ (LV1) ·· in which X and X are hydrogen, or Aliphatic group containing from 1 to 4 carbon atoms, R "stands for COPD, a COOX group where? ' is an optionally substituted C 1 -C 1 alkyl, optionally substituted aryl, or IS optionally substituted benzyl group by reacting it with an organometallic compound, preferably with the Grignard reagent of general formula X.VXI). 20 - in which R ' ² is 1-ol X, chloro, bromo or iodo and X * represents an X 6r- _f bromo or iodine intermediate of formula (XVXXX) or (X.XX) 25 P-1U9 tv ?; r. 09? 9 11500023 ~ on which Η, ky R 'stands for fantasy: cjcGca-aa and ν ⁵ ' stands for chlorine, kebab, or zebra. 2. The process according to claim 1, wherein the solubility of the sieves of the compounds of the formula WXI is inactivated by the salts and complexes of the atmic isms, in particular 16 stakes or beings, preferably fish, Cpb; bp; _: jaCl ··· where foodie1 self picture in 1 ef I-ry healthy ^{appetite? I3} and ih jelénkééa this one, ígénypohtban oeghstAsózott> 2ö <> & < 1, The ophthalmic signaling agent of claim L or hunger, which is a (LVI) non-lethal formula - ayglybene ah: Rh 3 / denotes the opening of the midin trap (entrapped in claim 1 "(LVXX'h formula erignato reaaganp - where k is i-oct 11-osnspot t ee, o is the above '\', <LVl ni> biesieééiaay - · in which Rh klj hl present delay 1. Demand point para effect hl R ² cr ' ^x o CHgGHh? - OSS ^ OaOhHNXZS PJ419 lantern) Pl 500023 4. The process of claim b, claim 2 wherein ye.llaoewe 'is that the opening of your aziridine ring (XX, VXX' ') as defined in claim 1 of formula (XVX) is wherein Grignard reagents - in which te * represents chlorine ···, brooch or iodine 10 X ^; denotes chlorine, brooch, or yo ·· and the product is iLXX). R · R ^s te Ο Ό L X) tex'te, ... you <. ite N H - in which 15, te 'and te are not defined in claim 1 and E ⁴ 'is a nucleus of the nucleus, the node, or the iodine, The process according to claim 4, characterized in that the intermediate LXX) is further converted to the intermediate intermediate of the formula (ΧΛΑΕΣΧ), wherein in each of the general fields of .20, the phosphorus agents are as defined in claim 1, nteonte 1 ~ te. te-tesbm _e o.teeki'te rv ^ rter ,. te - <'b'<from zinc-organic reagents of general formula in which X would be chlorine, orom, or iodine: 25 transition metals, preferably palladium catalysts. P-1419 / I put it: te δ, Method 4, wherein the intermediate IIIIXj is further converted to a 1-octane reaction mixture with palladium catalyst, or KHS. which is converted to the intermediate of formula (X.VXXX) in the next step, where in the general formulas 10 oh, p '·,; p, lead ^{Λ is as} defined in claim 4. A process according to any one of claims 1 to 6, wherein the intermediate is of the formula: - in which? P ^: represents C00r '^; group where R ' ^1J ' is a tert-butyl group or at least 11, and, & lt ^; A n ^{&gt;< /} RTI & gt ^; is a 1-oxide group, chlorine, htom, or iodine, S, The 1, -?. A process according to any one of claims 1 to 3, characterized in that it has the formula (LYXIII) 7-1419 2 0 16,03,16 · ύ '-X X, CHa CH < Z \ Oh! i .z X. NH-COO → benzyl intermediate was prepared 1, - r. sexve according to any one of claims 1 to 11, that t Χ »ΪΧ ') 11 11 a 1 η image 1 e t Crb CH3 X 0 X _r , 'X''''NCOO-P ⁵ 5 5 ia "is ámeryPen klór'- ·, gróra-, and desire ^{jééátom:, f} represent tert-butyl 1 - before or Benoit cnopgrt ö 1 nte d coin 1 has reached the 11 iTun k. The process according to claim A, wherein the aura signal is a compound of the formula Ι.3ΠΧ '} CH 5 OH; X. O G L J> XNH - CÖÖ ~ X í <-hz> ·· η-ΗΧΙ " - in which X is a terior-bnti1-desirable bentiX group.