FI56688C - METHOD OF FRAMSTERATION OF METHYL-N-ACETYL-2,3,4-TRI-O-ACETYL-7-DEOXY-7-SNRXR3-ALPHA-THIOLINCOSAMINIDER SOM AER ANVAENDBARA FOER FRAMSTAELLNING OF AV-7-DEOXY-7-RS - Google Patents

Description

• Member ΓΒ1 mt NOTICE OF PUBLICATION

[B] (11) UTLÄGGNINGSSKRIFT 56688 • C .... Patent granted on 10 03 1990 '' Patent meddelnt (51)>. P. * / Lnt.CI. * O 07 H 15/16 FINLAND I — Fl N LAND ( 21) Patent Application — Pat «ntans6kning 1700/72 (22) Application Pipe — Ansöknlnjtdaj lU.06.72 ^ ^ (23) Initial Pipe — Glltighatsdag lU · 06> 72 (41) Tullut | ulkl ** k * l — Bllvlt offentllf 2U.12.72

National Board of Patents and Registration of Finland oeh r.girt.ntyr.li.n <*> ÄÄS "Jl30.11.T9 (32) (33) (31) Privilege claimed — Bagird prlorltet 23.06.71 i2.O7.7i, i5.ll .7i USA (US) 156IOO I61909, 198990 - (71) The Upjohn Company, 301 Henrietta Street, Kalamazoo, Michigan, USA (US) (72) Brian Bannister, Kalamazoo, Michigan, USA (US) (7U) Berggren Oy Ab (5U) Process for the preparation of methyl-N-acetyl-2,3, U-tri-O-acetyl-7-deoxy-7-SnRXR3-0 (i-thiolinkosaminides - useful in the preparation of 7-deoxy-7-RSn-lincomycins - The present invention relates to the preparation of methyl N-acetyl-2,3, U-tri-O-acetyl-7-deoxy-7-SnRXR3 ~ <¥ -thiolinkosaminide, which is further preferred for the preparation of 7-deoxy-7wRSn-linkomyciner. relates to a process for the preparation of methyl-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7-SnRXR3-? -thiolincosamides of the formula ch3 - useful in the preparation of 7-deoxy-7-RSn lincomycins -S -R, -XR, n 1 3 ch3conh -

CH 2 COO r-O I

3> 1 \ OCOCH ./f SCH3 OCOCH3 where n is 1, 2 or 3, R1 is a saturated aliphatic hydrocarbon radical having up to 5 carbon atoms, an unsaturated aliphatic hydrocarbon radical having 2 or 3 carbon atoms, a cycloaliphatic hydrocarbon radical having 5 or 6 carbon atoms or an aromatic hydrocarbon radical A hydrocarbon radical having 6 or 7 carbon atoms and 2,56668 XR3 is hydrogen or a hydroxyl, thiol, methoxy, methylthio, acetoxy or acetylthio group.

The compounds of formula I are prepared by heating acetylated methyl-N-acetyl-6,7-aziridino-6-deamino-7-deoxy-o <-thiolincosamide in the presence of glacial acetic acid or another anhydrous low alkaline or anhydrous benzoic acid or other arene acid having up to 12 carbon atoms. , of the formula yfi-, CH3CON ^ ^ ch3coo / ° 11

With O 3 OCHCH 3 sulfide of the formula R 3 X -R 1 -Sn-R 2 -YR 2, where n, R and XR 3 are as defined above, R 1 represents a saturated aliphatic hydrocarbon radical having up to 5 carbon atoms. unsaturated aliphatic hydrocarbon radical having 2 or 3 carbon atoms, a cycloaliphatic hydrocarbon radical having 5 or 6 carbon atoms or an aromatic hydrocarbon radical having 6 or 7 carbon atoms, and YR1 represents hydrogen or hydroxyl, thiol, methoxy, acetyl, acetylthio group.

If n is greater than 1, the group R 2 -YR 2 must be a radical which readily forms a carbonium ion. Thus, the aziridine ring is opened to give methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7-SnRXR3-® -thiolincosamides of formula I.

Removal of the acetyl groups by hydrazinolysis in a manner known per se (see U.S. Patent No. 3,179,565) gives methyl 7-deoxy-7-RS-o (thiolincosaminide).

It is known that 7-SH analogs can be prepared by heating an aziridino compound of formula II with an acetyl group. in place of hydrogen, with hydrogen sulfide (U.S. Patent No. 3,554,551). Until now, it has not been possible to replace S-hydrogen directly or indirectly.

3,56668

It is also known that 7-OR analogs can be prepared by reacting a compound of formula II with an alcohol in the presence of an acid. Attempts to make sulfur analogs by replacing alcohol with mercaptan have failed.

It has now been found that the compounds of formula II undergo sulphidolysis when heated with sulphide (mono, di, tri or tetra) in glacial acetic acid or other anhydrous low alkanoic acid or anhydrous benzoic acid or other arene acid having up to 12 carbon atoms. The reaction is likely to proceed as follows: CH3 ίΗ3 CH3 f ® ch3 X \\

Acti HOAc AcN R ~ S - S-R --SR

T- - »η— ^ θ ->

AcNH-- ΛοΝΗ-- + ROAc

The reaction with the mixed sulfide can be considered to take place as follows: 4,06688 CH3 CH-.

--Με j ySn3 --S-isoPr

AcNH - S - CH

© ^ h3 © OAc, AcNH-- (SH2> + MeOAc

--SME

// CH3

AcNH - + (?) CH Ac§ _ \> isoPrOAc CH3

In the case of polysulfide, the reaction proceeds as follows pv / C) Ac CH3 CH3 / CH3

AcN * ^ Et2Sn ^ - SEt ^ n SEt ^ -HOAc Θ - »

AcNH--

AcNH--

With a mixed sulfide or an additional compound, namely a disulfide, for example, ch3 CH3 S ^ R 'is obtained.

h ^ - --S-R

AcN ^ dc p i Θ

Θ \ - RS "R

AcNH-- ys affects thio- -

s' style AcO W

ch3 K

CH3

--SnR '--SR

AcNH --- ACNH-- + R © + AcOSR '$ 6668

Polysulfide formation occurs when R and / or R 'is a radical that readily forms a carbonium ion, e.g., tert-butyl or allyl. In the case of tert-butyl, the carbonium ion can donate a proton to form isobutylene.

All of the refined sulfides provide the desired product simply by heating methyl N-acetyl-2,3,4-tri-O-acetyl-6,7-aziridino-6-decamino-7-deoxy-α-thiolincosaminide to the appropriate with sulphide in glacial acetic acid or other anhydrous low alkanoic acid or anhydrous benzoic acid or other arene acid containing up to 12 carbon atoms, e.g. propionic or butyric acids.

Preferably, a solvent boiling at about 70-110 ° C is used.

Excess sulfide is usually used for this purpose. If desired, solvents such as dioxane, carbon tetrachloride, benzene or toluene may be used, and preferably with sulfides boiling above about 110 ° C.

The ratios are not critical for the reaction, but are critical for the yields. The best yields are obtained with about 3-7 equivalents of acid combined with a substantial excess, at least twice the amount of sulfide. This is another advantage of using sulfide as a solvent. When using a sulfide, such as methyl sulfide, which boils so low as to give a reaction mixture boiling at reflux below 70 ° C, an overpressure may be used if it is such that the reaction mixture boils above about 110 ° C. Otherwise, it is preferably heated to reflux.

The reaction mixture can be treated by methods known in the art, such as countercurrent partitioning, chromatography, and solvent extraction or crystallization.

The starting compounds of formula II exist in two epimeric forms: 6 56688 "H 3 -ch 3 CH 3 CO-N 2 CH 3 CO-1

CH 2 COO / -O CH-COO> -O

f N ",> * f N" s \ | | / SCH3 \ | _ysCH3 o'coch3 ococh3 - 6 (R), 7 (R) -form 6 (R), 7 (S) -form

An inversion occurs in the reaction. For example, when methyl sulfide is reacted with methyl N-acetyl-2,3,4-tri-O-acetyl-6 (R), 7 (R) -aziridino-6-deamino-7-deoxy-α-thiolincosaminide, methyl-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7 (S) - (methylthio) -α-thiolinkosamine.

The starting sulfides of the formula R3X-R1-Sn-R2-YR4 are known compounds.

The invention is described in more detail below by means of examples in which parts are given by weight, except for solvent ratios or unless otherwise stated and the c.g.s. system is used unless otherwise stated.

Example 1

Methyl-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7 (S) - (methylthio) -g-thiolincosamidine--3 CH3

AcdT ^ SMe

AcNH--

AcO t-O

f \ -— ^ -ApO / 0 yl-p * Xe

OAc I I

OAc 7 $ 6688

A mixture of 5.0 g (1 molar equivalent) of methyl N-acetyl-2,3,4-tri-O-acetyl-6 (R), 7 (R) -aziridino-6-deamino-7-deoxy- α-thio-3-lincosaminide, 50 cm of methyl sulfide and 5.25 g (7 molar equivalents) of glacial acetic acid are heated in a Pyrex test tube for 20 hours on a steam bath. The volatiles are removed from the pink reaction solution by distillation at 100 ° C, the residue is dissolved in methylene chloride and mixed with an excess of saturated aqueous sodium bicarbonate solution. Washing the organic layer with water, drying over anhydrous sodium sulfate and removal of the solvent on a rotary evaporator at 40 ° C / 7 mm Hg gives a pink solid (5.92 g) in which, according to thin layer chromatography (SiO 2 gel, 1 acetone: 1 Skellysolve B) no more starting material and a new main zone with a lower Rf value. Skellysolve B is a technical hexane.

By countercurrent partitioning of this solid in system 1 with your ethanol, hydrogen acetate: 2 cyclohexane gives methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7 (S) - (methylthio) -α-thiolincosamide, which has a K- value is 1.21, as colorless rods from ethyl acetate-Skellysolves B and had the following properties: m.p. 225-226 ° C.

[α] D + 225 ° (c, 0.9876, CHCl 3)

Analysis: Calculated for c 18 H 21 Cl 2 N 2: C 47.88, H 6.47, N 3.10, S 14.20, molecular weight 451.55.

Found: C 47.87, H 6.49, N 3.19, S 14.31. molecular weight (mass spectrum, M +) 451.

^ Example 2

Methyl N-acetyl-2,3,4-tri-0-acetyl-7-deoxy-7 (S) - (etyylitlo) -q-tiolinkosaminidi

Following the procedure of Example 1, but substituting ethyl sulfide for methyl sulfide and heating at reflux for 7 hours, methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7 (S) - (ethylthio) -α is obtained. -thiolinkosaminide having the following properties: K = 1.85 (same solvent system) m.p. 236-237 ° C.

Z 'q_7D + 215 ° (c, 0.95, CHCl 3)

Analysis: Calculated for C 18 H 31 O 6 N 2 O 2: δ 56688 C 49.01, H 6.71, N 3.01, S 13.77,

Found: C 49.18, H 6.47, N 3.41, S 13.17.

This compound is also obtained with a K value of 6.15 in the countercurrent distribution of Example 12.

Example 3

An alternative method to Example 2

Replacing ethyl sulfide with ethyl disulfide and heating in an oil bath at 110 ° C for 20 hours gives the same 7 (S) - (ethylthio) compound, but in higher yield. ~

Example 4

Methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7 (S) (propylthio) -g-thiolincosamide

By proceeding as in Example 1, but replacing methylsulfide with methylpropyl sulfide, ethyl acetate is obtained from: Skellysolves B methyl-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7 (S) - (propylthio) - α-Thiolinkosaminide as colorless needles having the following characteristics:

mp. 259-261 ° C

[α] 25 D + 20 3 ° (c, 0.96, CHCl 3)

Analysis: Calculated for C 20 H 33 O 8 NS 2: C 50.08, H 6.93, N 2.92, S 13.37.

Found: C 49.89, H 6.96, N 3.02, S 13.41.

K = 3.10 (same solvent system).

The corresponding 7 (S) - (methylthio) compound with a K value of 1.32 is also obtained in a ratio of 1 part to 3 parts per 7 (S) - (propylthio) compound.

Example 5

Alternative to Example 4

By proceeding as in Example 2, but substituting ethyl sulfide for propyl sulfide, methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7 (S) - (propylthio) -α-thiolincosaminide is obtained.

Example 6

Methyl N-acetyl-2,3,4-tri-0-acetyl-7-deoxy-7 (S) - (isopropyl-thio) -a-tiolinkosaminidi

By proceeding as in Example 2, but substituting methyl isopropyl sulfide for ethyl sulfide 9 S6668, methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7 (S) - (isopropylthio) -α-thiolinocosaxninide is obtained from ethyl acetate. . It crystallizes as colorless needles having the following properties: K = 2.94 in a system 1 ethanol / water: 1 ethyl acetate: 2 cyclohexane m.p. 274.5 to 275.5 ° C.

[Α] D + 200 ° (c, 0.87, CHCl 3)

Analysis: Calculated for C20H33 ° 8NS2! ~ C 50.08, H 6.93, N 2.92, S 13.37.

Found: C 49.79, H 6.95, N 2.78, S 13.60.

The 7 (S) -methylthio compound (K = 1.32) is also formed in a ratio of 1.5 methylthio per isopropylthio.

Substitution of methyl isopropyl sulfide with isopropyl disulfide gives only methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7 (S) - (isopropylthio) -α-thiolincosaminide.

Example 7

Methyl N-acetyl-2,3,4-tri-0-asetyvli-7-deoxy-7 (S) - (cyclohexyl-lithio) -g-tiolinkosaminidi

By proceeding as in Example 1, but replacing methylsulfide with cyclohexylmethylsulfide and heating in an oil bath at 115 ° C for 24 hours, methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7 (S) - (cyclohexylthio) -α-thiolincosaminide (K = 5.95 using system 1 ethanol: 1 water: 1 ethyl acetate: 5 cyclohexane) as colorless prisms from ethyl acetate and having the following "properties: mp 248-250 ° C.

[Α] D + 184 ° (c, 0.86, CHCl 3)

Analysis: Calculated for C 23 H 37 ONS 2: C 53.15, H 7.18, N 2.70, S 12.34.

Found: C 53.27, H 7.28, N 2.79, S 11.92.

The corresponding 7 (S) - (methylthio) compound (K = 0.57) and otherwise according to the compound of Example 1 are also obtained in a ratio of about 1 part for each 5 parts of the 7 (S) -cyclohexylthio compound.

56668 10

Example 8

Methyl N-acetyl-2,3,4-tri-0-acetyl-7-deoxy-7 (S) - (Cyclopentyl-lithio) -g-tiolinkosaminidi

By proceeding as in Example 1, but replacing methyl sulfide with methyl cyclopentyl sulfide and heating in an oil bath at 100 ° C for 16 hours, methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7 (S ) - (cyclopentylthio) -α-thiolincosaminide with a K value of 4.0 using 1 ethanol: 1 water: 1 ethyl acetate: 3 cyclohexane.

It is obtained as colorless crystals from ethyl acetate and has the following properties: m.p. 265 to 265.5 ° C.

[α] D 7 + 187 ° C (c, 0.99, chloroform)

Analysis: Calculated for C 22 H 35 O 8 NS 2: C 52.25, H 6.98, N 2.77, S 12.68.

Molecular weight 505.64.

Received; c 52.07, H 6.88, N 2.68, S 12.62.

Molecular weight (mass spectrum, Mj 505.

When methylcyclopentyl sulfide is replaced by cyclopentyl disulfide, the same compound is obtained.

Example 9

Methyl N-acetyl-2,3,4-tri-0-acetyl-7 (S) - (butylthio) -7-deoksl-a-tiolinkosaminidi

Following the procedure of Example 3, substituting butyl disulfide for ethyl disulfide gives methyl N-acetyl-2,3,4-tri-O-acetyl-7 (S) - (butylthio) -7-deoxy-α-thiolinincosaminide (K = 3.35 , 1 ethanol: 1 water: 1 ethyl acetate: 3 cyclohexane) as colorless needles from ethyl acetate and with the following properties: m.p. 234.5 to 235 ° C.

Z "α7D + 197 ° (c, 0.51, CHCl 3)

Analysis: Calculated for c 21 H 35 ° 8NS 2! C 51.09, H 7.15, N 2.84, S 12.99.

Found: C 51.05, H 7.21, N 2.63, S 12.76.

Example 10

Part Pk Methyl-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7 (S) - (2-hydroxy-ethylthio) -ct-thiolinkosamide 11 56688

By proceeding as in Example 1, substituting 2-hydroxyethylmethyl sulfide for methyl sulfide and heating on a steam bath at 100 ° C for 5 hours, methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7 (S) - ( 2-hydroxyethylthio) -α-thiolincosaminide (K = 0.97, 1 ethanol: 1 water: 1 ethyl acetate: 0.5 cyclohexane) as colorless needles from ethyl acetate-Skellyolvol B and with the following properties: m.p. 226-228 ° C.

[Α] D + 185 ° (c, 1.00, CHCl 3)

Analysis: Calculated for C 19 H 31 GNS 2: C 47.38, H 6.49, N 2.91, S 13.32.

Found: C 47.18, H 6.79, N 2.86, S 12.73.

Part B: Methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7 (S) - (2-acetoxyethylthio) -α-thiolincosamide

By proceeding as in Example 1, substituting 2-acetoxyethylmethyl sulfide for methyl sulfide and heating on a steam bath at 100 ° C for 5 hours, methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7 (S) is obtained. - (2-α-acetoxyethylthio) -α-thiolincosaminide (K = 0.53, 1 ethanol: 1 water: 1 ethyl acetate: 3 cyclohexane) as colorless needles from ethyl acetate-Skelly lol B B and with the following properties:

Sp. 206-207 ° C.

Λ max + 80 ° (c, 0.79, CHCl 3)

Analysis: Calculated for <-21H33 ° 10NS2: C 48.17, H 6.35, N 2.68, S 12.25.

Found: C 48.12, H 6.37, N 2.58, S 11.95.

Example 11 "Methyl N-acetyl-2,3,4-tri-Q-acetyl-7 (S) - (tert-butylthio) -7-deoxy-g-thiolincosaminide

By proceeding as in Example 1, substituting tert-butyl-2-mercaptoethyl sulfide for methyl sulfide and heating in an oil bath at 100 ° C for 16 h, crude methyl N-acetyl-2,3,4-tri-O-acetyl-7 (S) is obtained. - (tert.butyylitio) -7-deoxy-a-tiolinkosaminidia.

Countercurrent partitioning of 1 ethanol: 1 water: 1 ethyl acetate / cyclohexane gives methyl N-acetyl-2,3,4-tri-O-acetyl-7 (S) - (tert-butylthio) -7-deoxy-α-thiolinincosaminide. K-ar-volla 2.38. It is obtained as small colorless needles from ethyl acetate and has the following properties: 12 S6666

Sp. 272-273 ° C.

+ o7d + 187 (c, 0.64, chloroform)

Analysis: Calculated for C 18 H 18 N 2 O 3; C 51.09, H 7.15, N 2.84, S 12.99.

Molecular weight, 493.63.

Found: C 51.19, H 7.28, N 2.95, S 13.13.

Molecular weight (mass spectrum, M +) 493.

The same compound is obtained, but in a lower yield than the methyl sulfide of Example 1 is replaced by tert-butyl sulfide.

Example 12

Methyl N-acetyl-2,3,4-tri-0-acetyl-7-deoksl-7 (S) - (etyyliditio) -g-tiollnkosaminidi

By proceeding as in Example 1, substituting tert-butylretyl disulfide for methyl sulfide and heating in an oil bath at 100 ° C for 16 hours, a crude product containing methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy- 7 (S) - (etyyliditio) -a-tiolinkosaminidia.

Countercurrent distribution of this feedstock in a system of 1 ethanol: 1 water: 1 ethyl acetate: 3 cyclohexane gives methyl 4-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7 (S) - (ethyldithio) -a -thiolincosaminide in a mixture of methyl-4-acetyl-2,3,4-tri-O-acetyl-7 (S) - (tert-butylthio) -7-deoxy-α-thiohydrosaminamide in a ratio of 30/70. The K value of this mixture is 2.57. Both products are separable by steam phase chromatography and are distinguished from each other by the fact that the former has a UV absorption at 245 nm, ε, 546 while the latter has no UV absorption. The former compound has a molecular ion of m / e 497 in the mass spectrum compared to the calculated value of 497.65. The latter compound is identical to that obtained in Example 11.

Example 13

Methyl N-acetyl-2,3,4-tri-0-acetyl-7 (S) - (tert.butyyliditio) -7-deoxy-a-tiolinkosaminidi

By proceeding as in Example 3, substituting tert-butyl disulfide for ethyl disulfide gives methyl N-acetyl-2,3,4-tri-O-acetyl-7 (S) - (tert-butyldithio) -7-deoxy-α-thiolinkosaminide as small colorless Ethyl acetate in sticks: Skellysolvesta B and having the following characteristics:

Sp. 241-242 ° C.

13.56 & 8 COn + 220 ° (c, 0.56, CHCl3).

(K = 7.35, 1 water: 1 ethanol in your ethyl acetate: 3 cyclohexane) Analysis: Calculated for C 21 H 35 O 8 N® 3: C 47.98, H 6.71, N 2.67, S 18.30.

Found: C 48.03, H 6.65, N 2.65, S 18.65.

Molecular weight (calculated): 525.70

Found: (mass spectrum, M +): 525.

This compound is also obtained with a K value of 1.43 in the countercurrent distribution of Example 12.

Example 14 Alternative to Example 1 Following the procedure as in Example 3, substituting methyl tert-butyl sulfide for ethyl disulfide affords methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7 (S) - (methylthio). -α-thiolincosaminide, which is the same compound as the compound obtained in Example 1. The advantage of this alternative method is that the desired product is obtained in higher yields.

Example 15 Alternative to Example 1

Following the procedure as in Example 3, substituting ethyl disulfide-1,2-bis (methylthio) ethane gives methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7 (S) - (methylthio) -α -thiolinkosaminide, which is identical to the product obtained in Example 1. This method also gives better yields and not surprisingly does not yield any 7 (S) - / 2- (methylthio) ethylthio / compound.

Example 16

Alternative to Example 1

By proceeding as in Example 3, substituting 2- (methylthio) ethanethiol for ethyl disulfide gives methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7 (S) - (methylthio) -α-thiolincosaminide, which is the same compound as the compound obtained in Example 1 and methyl-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7 (S) -N- (2-methylthio) ethylthio7-α-thiolincosaminide in a ratio of 80 parts of the former and 20 parts of the latter. Countercurrent distribution to system 1 ethanol: 1 water: 1 ethyl acetate: 3 cyclohexane gives the latter compound with a K value of 1.84. It is obtained as colorless needles from ethyl acetate-Skelly's flask B and had the following properties: 14,56668 m.p. 236-237 ° C.

[Α] D + 183 ° (c, 0.93 chloroform)

Analysis: Calculated for C 20 H 33 O 8 NS 2: C 46.94, H 6.50, N 2.74, S 18.80.

Molecular weight 511.67.

Found: C 46.96, H 6.92, N 2.49, S 18.38.

Molecular weight (mass spectrum, M +) 511.

Example 17

An alternative to Example 1 ~

By proceeding as in Example 3, substituting 4- (methylthio) butanethiol for ethyl disulfide gives methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7 (S) -methylthio-α-thiolincosaminide, which is identical to the compound of Example 1.

4- (Methylthio) butanethiol is obtained by mono-S-methylation of 1,4-butanedithiol using one equivalent of sodium hydroxide and methyl iodide in ethyl alcohol.

Example 18

Alternatives to Example 3

By proceeding as in Example 3, substituting ethyl trisulfide for ethyl disulfide and heating in an oil bath at 100 ° C for 16 hours, the same 7 (S) -ethylthio compound is obtained in good yield.

Example 19

Methyl-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7 (S) - ([3-methylthio] propylthio) 7 '- α-thiolincosamide

Following the procedure as in Example 15, substituting 1,3-bis (methylthio) propane for ethyl trisulfide gives methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7 (S) - (T3-methylthio) propylthio. / -a-tiolinkos-aminidi.

By countercurrent distribution and using the same solvent system as in Example 16, the above compound with a K value of 2.24 is obtained. It crystallizes from ethyl acetate as colorless needles having the following properties: m.p. 211-212 ° C.

^ ~ α_7ρ + 181 ° (c, 1.1, chloroform).

Analysis: Calculated for C 21 H 31 O 5 N 3 O: S6668 C 47.98, H 6.71, N 2.67, S 18.30.

Molecular weight 525.70.

Found: C 47.97, H 6.78, N 2.62, S 17.73.

Molecular weight (mass spectrum, M) 525.

Example 20

By proceeding as in Example 16, substituting 2- (methylthio) ethanethiol for 2- (methylthio) ethanethiol acetate gives methyl N-acetyl-2,3,4-tri-O-acetyl-7 (S) - (2-acetylthioethylthio). ) -7-deoxy-α-tiolinkosaminidia. Countercurrent partitioning using the same solvent system as in Example 16 gives this compound with a K value of 1.55.

It is obtained in the form of small colorless needles from ethyl acetate and with the following properties: m.p. 198-199 ° C.

[α] D + 168 ° (c, 1.0, chloroform).

Analysis: Calculated for C 21 H 33 O 9 NS 3: C 46.73, H 6.16, N 2.60, S 17.63.

Molecular weight 539.68.

Found: C 46.84, H 6.05, N 2.56, S 17.52.

Molecular weight / (mass spectrum, M +) -HCHS7 493.

Example 21

By proceeding as in Example 1, replacing methyl sulfide with 2-methoxyethylmethyl sulfide and heating in an oil bath at 100 ° C for 16 hours, methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7 (S) - (2-methoxyethylthio) -a-tiolinkosaminidia. Countercurrent distribution using 1 ethanol: 1 water: 1 ethyl acetate: 2 cyclohexane as the solvent system gives this compound with a K value of 0.88. It is obtained as colorless needles from ethyl acetate and has the following properties: m.p. 225-227 ° C.

[α] 25 D + 171 ° (c, 0.90, chloroform).

Analysis: Calculated for C 20 H 23 O 9 NS 2: C 48.47, H 6.71, N 2.83 ·, S 12.94.

Molecular weight 495.60.

Found: C 48.72, H 6.82, N 2.79, S 12.77.

Molecular weight (mass spectrum, M +) 495.

Example 22

Methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7- (SJ- (vinylthio) -α-thiolincosaminide 06668 16

By proceeding as in Example 1, replacing methyl sulfide with methyl vinyl sulfide and then heating at 100 ° C for 16 hours, methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7 (S) - (vi) is obtained. -nyylitio) -α-tiolinkosaminidia. Countercurrent partitioning in a solvent system of 1 ethanol: 1 water: 1 ethyl acetate: 3 cyclohexane gives this compound with a K value of 1.57. It is obtained as colorless needles from ethyl acetate-Skellysolvol B with the following properties:

Sp. 215.5 to 216 ° C.

[α] D / D + 168 ° (c, 0.79, chloroform).

Analysis: Calculated for C 19 H 29 O 8 N 2 O 2: C 49.23, H 6.31, N 3.02, S 13.83.

Molecular weight 463.56.

Found: C 49.06, H 6.39, N 3.13, S 13.33.

f.

Molecular weight (mass spectrum, M) 463.

Example 23

Methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7 (S) - (allylthio) -q-thiolinincosamide and methyl N-acetyl-2 / 3,4-tri-O -acetyl-7-deoxy-7 (S) - (propenylthio) -α-thiolinkosaminide

By proceeding as in Example 1, substituting allyl sulfide for methyl sulfide and heating at 100 ° C for 16 hours, methyl N-acetyl-2,3,4-tri-O-acetyl-7 (S) - (allylthio) -7-deoxy- a thiol-kosaminidi. Methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7 (S) - (propenylthio) -α-thiolinincosamide is also obtained. Countercurrent partitioning using a solvent system of 1 ethanol: 1 water: 1 ethyl acetate: 2 cyclohexane gives an allyl compound with a K value of 1.76 and a propenyl compound with a K value of 3.30. The allyl compound crystallizes from ethyl acetate-Skelly's flask B as colorless needles having the following properties:

Sp. 235-237 ° C.

Λ max + 194 ° (c, 0.63, chloroform)

Analysis: Calculated for C20H31N8NS2: C 50.29, H 6.54, N 2.93, S 13.43.

Molecular weight 477.59.

Found: C 50.10, H 6.67, N 2.79, S 13.00.

+

Molecular weight (mass spectrum, M) 477.

The propenyl compound is obtained as colorless needles from ethyl acetate-Skel lysol B, with the following properties: 17 56668

Sp. 273-275 ° C.

[Α] D 7 + 157 ° (c, 1.05, chloroform).

Analysis: Calculated for C 20 H 31 N 8 N 2 O 2: C 50.29, H 6.54, N 2.93, S 13.43.

Found: C 50.43, H 6.45, N 2.96, S 13.37.

Molecular weight (mass spectrum, M +) 477.

Example 24

Methyl N-acetyl-2,3,4-tri-0-acetyl-7 (S) - (allyyliditio) -7-deoxy-a-tlollnkosaminidi

The procedure of Example 1 is followed by replacing methyl sulfide with allyl disulfide and heating at 100 ° C for 16 hours and the product is chromatographed on silica gel using 1 ethyl acetate: to remove the polar desired product. Countercurrent partitioning of the latter using 1 ethanol: 1 water: 1 ethyl acetate: 3 cyclohexane as the solvent system gives methyl N-acetyl-2,3,4-tri-O-acetyl-7 (S) - (allyldithio) -cr-thiolincosaminide at K 66. It crystallizes from ethyl acetate as impermeable colorless prisms with the following properties:

Sp. 211-213 ° C.

7d + 251 (c, 1.00, chloroform).

Analysis: Calculated for C 20 H 31 O 8 NS 3: C 47.13, H 6.13, N 2.75, S 18.88.

Molecular weight 509.66.

Found: C 47.03, H 6.16, N 2.56, S 18.68.

Molecular weight (mass spectrum, M +) 509.

- An allyl thio analogue (A-21-allyl) is also obtained with a K value of 2.03.

Example 25

Methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7 (S) - (2,3-dihydroxypropylthio) -ot-thiolinkosamide

By proceeding as in Example 1, substituting 2,3-dl-hydroxypropylmethyl sulfide for methyl sulfide gives methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7 (S) - (2,3-dihydroxypropylthio) -a -tiolinkosaminidia. Countercurrent partitioning with 1 ethanol of your water: 1.5 ethyl acetate: 0.5 cyclohexane gives this compound with a K value of 0.91. It is obtained as colorless flakes from ethyl acetate and has the following properties: 56668 18

Sp. 255-257 ° C.

+ D + 164 ° (c, 0.67, chloroform).

Analysis: Calculated for C 20 H 33 O 10 NS 2: C 46.95, H 6.50, N 2.74, S 12.54.

Molecular weight 511.60.

Found: C 46.64, H 6.67, N 2.73, S 12.59.

Molecular weight (mass spectrum, M +) 511.

Example 26

Part A: Methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7 (S) -phenylthio) -α-aminosaminamide

By proceeding as in Example 1, replacing methyl sulfide with methyl phenyl sulfide, methyl N-2,3,4-tri-O-acetyl-7-deoxy-7 (S) - (phenylthio) -α-thiolincosaminide is obtained as fine colorless needles from ethyl acetate and with the following properties:

Sp. 275-276 ° (K = 3.17, 1 ethanol: 1 water: 1 ethyl acetate: 3 cyclohexane) / δ_7D + 164 ° (c, 0.53, CHCl 3)

Analysis: Calculated for C 23 H 23 N 2 O 2 = C 53.78, H 6.08, N 2.73, S 12.49.

Found: C 53.87, H 6.07, N 2.48, S 12.51.

£ 6668 19

Part B: Alternative method

By proceeding as in Part A, substituting benzylphenyl sulfide for methylphenyl sulfide gives the same compounds. This method has the advantage that it gives the product in higher yields.

Example 27

Methyl N-acetyl-2,3,4-tri-0-acetyl-7 (S) - (benzylthio) -7-deoxy-a-tiolinkosaminidi

Following the procedure as in Example 18, substituting benzyl sulfide for 2- (methylthio) ethane-thiol gives methyl N-acetyl-2,3,4-tri-O-acetyl-7 (S) - (benzylthio) -7-deoxy-α- tiolinkosaminidia.

Countercurrent partitioning using a solvent system of 1 ethanol: 1 water: 0.5 ethyl acetate: 3 cyclohexane gives this compound with a K-value of 1.38. It is obtained as lithium prisms from ethyl acetate-Skellysol water B and has the following properties:

Sp. 216-218 ° C.

[α] D + 161 ° (c, 1.07, chloroform).

Analysis: Calculated for C 24 H 33 O 8 N® 2: C 54.63, H 6.30, N 2.66, S 12.15.

Found: C 55.02, H 6.44, N 2.94, S 12.19.

Molecular weight calculated: 527.64

Molecular weight obtained (mass spectrum, M +): 527.

Example 28

Methyl N-acetyl-2,3,4-tri-0-acetyl-7-deoksi7 (S) - (2-hydroxy-phenylthio) -g-tiolinkosaminldi

By proceeding as in Example 18, substituting allyl-2-hydroxyphenyl sulfide for ethyl trisulfide affords methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7 (S) - (2-hydroxyphenylthio) -g- tiolinkosami-cyanide. Countercurrent partitioning in system 1 with ethanol water: 1 ethyl acetate / cyclohexane gives this compound with a K value of 1.54.

It is separated from the ethyl acetate as colorless rods and has the following properties:

Sp. 240-241 ° C.

[Tq] + 154 ° (c, 0.83, chloroform).

Analysis: Calculated for C 23 H 31 O 9 NS 25 C 52.16, H 5.90, N 2.65, S 12.11.

Molecular weight 529.62.

20

GB> 668

Found: C 52.23, H 5.92, N 2.72, S 11.99.

Molecular weight (mass spectrum, M +) 529.

Example 29

Methyl N-acetyl-2,3 / 4-tri-O-asetyvli-7-deoxy-7 (S) - (2-hydroxy-2-methylethylthio) -a-tiolinkosaminidi

By proceeding as in Example 1, substituting 2-hydroxy-2-methylethylmethyl sulfide for methyl sulfide and heating in an oil bath at 100 ° C for 24 hours, methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7 ( S) - (2-Hydroxy-2-methylethylthio) -α-thiolincosaminide (K = 1.0 L of ethanol in aqueous ethyl acetate: 0.75 in cyclohexane) as colorless prisms from ethyl acetate and with the following properties:

Sp. 246-251 ° C.

Z + qD + 171 ° (c, 0.88, CHCl 3) ·

Analysis: Calculated for C 20 H 33 O 9 NS 2: C 48.47, H 6.71, N 2.83, S 12.94.

Molecular weight 495.60.

Found: C 48.51, H 6.71, N 2.77, S 12.72.

Molecular weight (mass spectrum, M +) 495.

The starting 2-hydroxy-2-methylethylmethyl sulfide is prepared by heating 2-hydroxy-2-methylethyl bromide or 2-hydroxy-1-methylethyl bromide or a mixture of both with sodium methyl mercaptide in ethanol.

Starting from 2-acetoxy-2-methylethylmethyl sulfide instead of 2-hydroxy-2-methylethylmethyl sulfide, methyl 7 (S) - (2-acetoxy-2-methylethylthio) -N-acetyl-2,3,4-tri-O- acetyl-7-deoxy-α-thiolincosaminide, m.p. 199-200 ° C.

Example 30

Methyl N-acetyl-2,3,4-tri-0-acetyl-7 (S) - (3-acetoxypropyl-thio) -7-deoxy-a-tiolinkosaminidi

By proceeding as in Example 1, substituting 3-acetoxypropylmethyl sulfide for methyl sulfide gives methyl N-acetyl-2,3,4-tri-O-acetyl-7 (S) - (3-acetoxypropylthio) -7-deoxy-α-thiolinkos-ciminide. (K = 1.0, 1 ethanol: 1 water: 1 ethyl acetate: 2 cyclohexane) as colorless needles ethyl acetate: Skellysolvolv B and with the following properties: 21

Sp. 172.5 to 174 ° C. 566ββ / q_7D + 178 ° (c, 0.94, CHCl 3).

Analysis: Calculated for C22H35ONS2: C 49.15, H 6.56, N 2.61, S 11.93.

Found: C 49.31, H 6.58, N 2.68, S 11.83.

Example 31

Methyl 7 (S) - (4-acetoxybutylthio) -7-deoxy-α-thiolinkosamide By proceeding as in Example 1, substituting 4-acetoxybutylmethyl sulfide for 4-acetoxybutylmethyl sulfide and heating at 110 ° C for 20 hours gives methyl N-acetyl-2 , 3,4-tri-O-acetyl-7 (S) - (4-acetoxybutylthio) -7-deoxy-α-thiolincosaminide (K = 1.32, 1 ethanol: 1 water: 1 ethyl acetate: 2 cyclohexane) as fine needle bows from ethyl acetate-Skellysolvolv B and with the following properties:

Sp. 149-150 ° C.

[α] 25 D + 171 ° (c, 0.88, CHCl 3).

Analysis: Calculated for C 23 H 37 O 10 N® 2: C 50.07, H 6.76, N 2.54, S 11.62.

Found: C 49.97, H 6.86, N 2.50, S 11.35.

Example 32

Methyl N-acetyl-2,3,4-tri-O-acetyl-7 (S) - (5-acetoxypentylthio) -7-deoxy-α-thiolecosaminamide

Following the procedure as in Example 1, substituting 5-acetoxypentylmethyl sulfide for methyl sulfide and heating at 100 ° C for 16 hours gives methyl N-acetyl-2,3,4-tri-O-acetyl-7 (S) - (5-acetoxy-pentylthio). ) -7-deoxy-α-thiolincosaminide, having a K value of 1,94 l of ethanol: 1 aqueous ethyl acetate: 2 in cyclohexane and having the following properties crystallized from ethyl acetate-Skelly's solvate B:

Sp. 158.9 ° C (needles) / δ_7D + 169 ° (c, 0.60, CHCl 3)

Analysis: Calculated for C 24 H 39 O 10 N 2 O 2: C 50.95, H 6.95, N 2.48, S 11.34.

Found: C 50.88, H 6.98, N 2.41, S 11.22.

Example 33

Methyl N-acetyl-2,3,4-tri-0-acetyl-7 (S) - (2-asetoksisyklohek-syylitio) -7-deoxy-g-tlolinkosaminidi

Following the procedure as in Example 1, replacing methyl sulfide with 2-acetoxycyclohexylmethyl sulfide and heating at 100 ° C for 56668 for 16 hours gives methyl N-acetyl-2,3,4-tri-O-acetyl-7 (S) - (2-acetoxycyclohexylthio) -7-deoxy-a-tiolinkosaminidia. Countercurrent partitioning in a solvent system of 1 ethanol: 1 water: 0.5 ethyl acetate: 3 cyclohexane gave this compound with a K value of 0.80. It is obtained as colorless needles from ethyl acetate and has the following properties:

Sp. 205-206 ° C.

[α] D + 153 ° (c, 0.64, CHCl 3).

Analysis: Calculated for C 25 H 39 O 10 NS 2: C 51.97, H 6.80, N 2.43, S 11.10.

Molecular weight 577.70.

Found: C 51.82, H 6.87, N 2.29, S 11.12.

Molecular weight (mass spectrum, M +) 577.

Claims (1)

A process for the preparation of methyl-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7-SnRXR3? OC-thiolincosamines of the formula ch3- to 7-deoxy-7-RSn-lincomycins. -S —R, -XR ~ n 1 3 ch3conh-- CHoC00 / 0 1 YN \ _ / sch3 OCOCH3 where n is 1, 2 or 3, R1 is a saturated aliphatic hydrocarbon radical having up to 5 carbon atoms, an unsaturated aliphatic 2 or 3 carbon atoms cycloaliphatic hydrocarbon radical having 5 or 6 carbon atoms or an aromatic hydrocarbon radical having 6 or 7 carbon atoms and XR3 is hydrogen or a hydroxyl, thiol, methoxy, methylthio, acetoxy or acetylthio group, characterized in that the methyl-N -acetyl-2,3,4-tri-O-acetyl-aziridino-6-deamino-7-deoxy-thiolinincosamine diad of the formula CH, C0if / <^ CH3 3 \ _ CH-.COO A ° vk ) Np ^ c „3 OCOCH3 with a sulfide of formula R, XR.-S -R ~ -YR ,, where n, R1 and XR3 have the same meaning and above, R3 represents a saturated aliphatic hydrocarbon radical having up to 5 carbon atoms, an unsaturated aliphatic hydrocarbon radical having 2 or 3 carbon atoms, a cycloaliphatic hydrocarbon radical having 5 or 6 carbon atoms or an aryl radical having an aromatic 6 or 7 carbon atoms, , methoxy, methylthio, acetoxy or acetylthio.