JPS61238744A - Manufacture of (+)r-2-methyl-hexane-1,2-diol - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION Prostaglandins as a class have recently been the subject of intense research. Naturally occurring or synthetic prostaglandins are derivatives of brostanic acid and are involved in a wide range of biochemical actions, including cardiovascular, neurological, reproductive, renal and gastric responses. is elicited in animals. These responses can be produced by administering one or more of these prostaglandins in doses as low as about 10 ng/Kg body weight. Early isolation of these highly active compounds was accomplished primarily by extraction from mammalian tissues. However, such extraction methods are typically not commercially viable and do not provide sufficient quantities for proper pharmacological evaluation. Synthetic methods have evolved to the point where sufficient quantities can be produced entirely by chemical synthesis.

However, this method suffers from the disadvantage that it is inherently non-stereospecific and therefore laborious resolution procedures have to be carried out to obtain the desired optically active isomers. It is known in the art that most active prostaglandin derivatives have specific stereochemical configurations at each asymmetric carbon atom and/or double bond.

16-methyl-1,11α,16R8-trihydroxygest-3E-en-9·one (e.g. TR-4698
No. 4,132,738 [issued January 2, 1979 to K. Luender et al.] (References incorporated herein by reference) and framed prostaglandin analogs. TR-4698 is xyl C-1
It is a mixture of two isomers at the 6-position. This one
6-R isomer (i.e. 16R-methyl I A 1
16
However, it is unlikely that the racemic mixture or the 16-
It would be desirable to be able to synthesize the 16-R isomer in order to assess the degree of physiological activity, toxicity, etc. that can be attributed to them as opposed to that present in the 8 isomer alone. This consideration may also be of value when satisfying the regulatory authorities involved in new drug approvals for physiologically active drugs. Therefore, when it is ultimately incorporated into this molecule, it becomes a monomer rather than a isemic mixture.
It became desirable to devise a synthesis of intermediates with the required stereochemistry that provided only the 6-R isomer (TR-7133). The method taught here is (+)R-2-
Concerning the synthesis of methyl-hexane-1,2-diol (16-R isomer, intermediate for the preparation of TR-7133). The intermediate is prepared via an asymmetric/'i-rolactonization reaction utilizing L-proline as a chiral agent, which can be subsequently incorporated into the synthesis as described below.

Various techniques have been utilized in the production or isolation of physiologically active prostaglanone isomers. One such technique is to utilize a resolved intermediate with the appropriate stereochemistry at the chiral center for incorporation into the molecule. For example, Pappo et al.
Chemical, biochemical and pharmacological activities of prostanoids (
ChemistryyB iochemistry
and Pharmacological A
activity of prosta
nids) J, S, M, (l
t<-'7 (Roberts) and F. S heimann II.

Pages 17-26, bar is Mon Press (Perga
mwon Press), New York, 1978
taught the resolution of racemic 2-hydroxy-2-methyl-hexanoic acid via its 7-thyl ethylamine salt to produce chiral acetylenic alcohols. (This optically active acetylenic alcohol can then be incorporated as the "right hand" moiety of the prostagranone analog according to known techniques), however, racemic 2-hydroxy-2-methyl - Classical resolution of hexanoic acid is at best cumbersome and requires expensive optically active amines.

Y, 7 Fujimoto, J, Ya
dev) and C, Sih, Tetrahedron Letter
Another approach, taught by J.D. Ters), 21.1481 (1980), converts (−)S-2-methyl-hexane-1,2-diol to (+)citramaric acid (cit
ralolic acid) and then use chiral diols to produce the corresponding optically active acetylenic alcohols. A disadvantage of this method is that isolated microbial enzymes must be used to prepare citramaric acid from mesafonic acid.

S-s, Je@, S, flyer v (Ter
ashima) and Koda, Tetrahedron, 35.2337
(1970) and the papers cited therein describe an uncontrolled 10-lactonization reaction to prepare optically active α,β-disubstituted-bihydroxy acids from α-unsaturated acids. Teach us how to use ν・ru. However, the technique described there suffers from the drawback that it is not possible to obtain the resulting S-isomer of the α,α-disubstituted-α-hydroxy acid in high-1 optical purity.

For example, Jew et al. reported that when trans-2-methyl-2-butenoic acid is utilized as a starting compound, the R-isomer of the resulting 2-hydroxy-2-methylbutanoic acid is highly enriched relative to the S-isomer. It is taught to produce in ~1 major ratio (1!95:5, respectively). Similarly, when cis-2-methyl-2-butenoic acid was studied as a starting material, the R-isomer of the resulting 2-hydroxy-2-methylbutanoic acid still accounted for the predominant proportion, but the S-isomer (60:40 respectively).

The invention described herein is derived from methacroyl chloride (
+) Teach the preparation of R-2-methyl-hexane-1,2-7ol. As mentioned above, this intermediate is the optically active 16-R of prostagranone.

For example, it can be used to manufacture TR-7133.

The present invention provides stereospecific prostaglanone intermediates (+)
Concerning the product of R-2-methyl-hexane-1,2-diol. This method converts methacroyl chloride into L-
Reacting with proline in the presence of a base to produce an amide of formula. This amide is then reacted with N-bromo-succinimide in an aprotic polar solvent to produce a bromolactone of the formula. The bromolactone is then hydrolyzed with aqueous hydrobromic acid to produce the bromo acid of formula. The bromo acid is then reduced with a borane-tetrahydroctane mixture to produce the bromodiol of formula. This bromodiol is then treated with dimethoxy-propane and toluenesulfonic acid to produce the 7cetonide of formula. This acetonide is then reacted with dipropyl cuprate to produce the alkylated product of formula. This fullkylated product is then reacted with acidic aqueous tetrahydro7rane to form (+)R-2-
Methyl-hexane-1,2-diol is produced.

The process of the present invention provides for the production of (+)R-2-methyl-hexane-1,2-diol via an asymmetric halolactonization reaction using L-proline as the chiral agent. The reaction formula for producing this diol is shown in Table 1.

N-Metacroyl-L-proline is first prepared by adding methacroyl chloride slowly to an aqueous mixture of L-proline, sodium bicarbonate and diethyl ether (maintaining the pH throughout at about 10-11) and this mixture is Stir at ambient temperature for about 15 minutes to about 2 hours (Step A).

N-methacroyl-di-proline is then isolated according to conventional extraction techniques. Bromolactonization is then carried out as follows. N-bromosuccinimide (NB
S) is added to the L-proline derivative in an aprotic solvent, such as dimethylformamide (DMF), and then stirred at ambient temperature for about 12 to about 36 hours (Step B).

The resulting bromolactone is isolated and then heated with aqueous hydrobromic acid for about 15 to about 24 hours (about 100-110
°C) (Step C). The resulting bromo acid is isolated by conventional techniques and then reduced by treatment with a mixture of BH, in tetrahydrofuran (Step D). The mixture is stirred at ambient temperature for about 12 to about 24 hours, and then the reaction is stopped by the addition of a small amount of a mixture of tetrahydro7ran/water (about 1:1). The resulting bromodiol is then recovered by conventional techniques as described below.

Conobromophenol as nomethoxyprohane (DMP)
and a catalytic amount of toluenesulfonic acid at ambient temperature with agitation for about 8 to about 24 hours to protect the promonol as its acetonide (Step E).

A solution of n-propyllithium in anhydrous diethyl ether is prepared (maintained at about -40° C. under an atmosphere of inert gas) and then treated with CuCN. B.H.

Lipshutz et al., yr2 (19
See 81). The resulting cuprate solution is added to a solution of the above 7cetonides in diethyl ether (Step F) and the mixture is maintained at about 0° C. with stirring in an inert gas atmosphere for about 15 minutes to about 2 hours. This stirred mixture was then diluted with saturated aqueous ammonium chloride solution (p
8-9) and shake. The resulting alkylated product is recovered by conventional means and then treated with acidic aqueous tetrahydro7rane (Step G) to obtain the desired compound (Step G).
-2-methyl-hexane-1,2-diol is produced.

(+)R-2-methyl- produced by the method of the present invention
Hexane-1,2-diol can be utilized (according to known techniques) in the production of certain stereospecific prostaglanone analogs, as briefly described below. Using the procedure of Pappo et al. cited above, (+
) R-2-methyl-hexane-1°2-diol with the corresponding stereospecific acetylenic alcohol, i.e. 4
-Methyloct-1-yn-4R-ol. The reaction order is shown in Table 2.

Red 3, KF (in DMP) As shown in Table 2, (+)R-2-methyl-hexane-
The 1,2-diol is treated with tosyl chloride in pyridine to produce the monotosylate. Addition of a 3 equivalent excess of lithium triethylsilylacetylate (generated in situ) of the monotosylate produces an intermediate epoxide, which opens upon treatment with dimethyl sulfoxide (DMSO). Potassium heptadide (KF) in dimethylformamide
) followed by purification yields the desired stereospecific acetylenic 7 alcohol.

Kluender et al. (U.S. Pat. No. 4)
The above acetylenic alcohol is then converted to the corresponding iodovinyl alcohol, as taught by J. K., 132, 738, cited above). The hydroxyl functionality of the iodovinyl alcohol is protected with an acid-labile hydroxy protecting group (alternatively, the hydroxyl group of the acetylenic alcohol can be protected prior to conversion of the derivative alcohol to iodovinyl alcohol). 6 Then,
Hydroxy-protected iodovinyl alcohols are lithiated with t-butyllithium and reacted with complexes of solubilizing ligands of copper(1) compounds, such as (hexamethylphosphorustriamide)2-copper(1)pentyne. Or produces 7 lithium oparate. The orif/lithiouparate was then reacted with 4R-(tetrahydrobilan-2-yloxy)72-(7-tetrahydrobilan-2-yloxy)hebutyl]-2-cyclobentole/n to give TR =7133 to produce the ropyran-protected form of tetrahy. The protected form is then hydrolyzed with a weak acid to produce TR-71,33. As will be appreciated, optically active (+
) R-2-Methyl-hexane-1,2-diol can be used to prepare other prostaglandin analogs.

The invention is illustrated by the following examples.

Example 1 (+)R-2-Methyl-hexane-1,2-diol (a) N-methacroyl-prolinehyproline (42.0 g), NaHCO3 (148 g), H20
(680 ml) and diethyl ether in a bath at ambient temperature to pH 10.5-10.
7 and adjusted by adding water-reducing NaOH),
It was then treated in portions over 20 minutes with a solution of redistilled methacroyl chloride (40 ml) in diethyl ether (20 mJ). Additional aqueous NaOH was added as needed to maintain the pH between 10.5 and 1.0.7. All methacroyl chloride added (and pH
When the mixture stabilized), the mixture was stirred at ambient temperature for 20 minutes. The resulting immiscible phases were separated and the aqueous phase was extracted twice with 250 IIll portions of diethyl ether. The combined organic extracts were washed with 820 (5 omz), the aqueous extract was added to the aqueous phase, and this phase was then acidified to pH 1 with aqueous HCI, then 250 mj! The combined ethyl acetate extracts were washed with approximately 100 g of brine (saturated aqueous sodium chloride solution) and then dried over Na2SO4. The resulting solution is filtered, concentrated in vacuo to approximately 230 d, then heated to boiling, diluted with hexane (80 ml) and cooled. Upon cooling, the desired N-methacroyl L~proline crystallized spontaneously as large chunks of white columnar crystals (5
1.3B). A portion of the first crop was recrystallized twice from ethyl acetate to obtain a sample for analysis. Melting point 102-104.
5℃6 Spectral characteristics: 1r (CHC13) 2970.1712.1610.1
455.1440.1200.915 cm-';n
mr (CD CI,) δ11.7 (s, IH), 5.0
5-5.40 (n+, 2H), 4.60 (t, J=6,
IH), 3.64 (t, J=6.2H), 1.90-2
．． 50 (m, 4H), 1. 9 6 (s,
3H);C”nmr(CDCI*)ppm174
゜7, 171.9, 140.5, 1 17.5, 59゜1.49゜5.2869.25.0. 19.6; [α
] =-136,41 (C=1.111, CHCI,
), the optical rotation changes with concentration.

Calculated value for analysis C, H,, No. 3: C159,0
0;H1? , 15; N, 7,65° Actual value: C 158° 90; H, 6,99; N, 7.67° 36.6 g of the title compound of Example 1(a) was dissolved in 5OOII
Dry (4 people) dimethylformamide, maintained at ambient temperature under an atmosphere of inert gas and protected from light) and recrystallized N-bromosuccinimide (7 people).
1.2 g). The resulting mixture was stirred for approximately 20 hours, then poured into a mixture of saturated aqueous sodium bicarbonate (21) and ethyl acetate (800 mj) and shaken vigorously. The resulting immiscible phase was separated, and the aqueous phase was
The 00 mn portion was extracted three times with ethyl acetate. 125mj of the combined ethyl acetate extracts! saturated Na2S in the part of
20. Extracted 8 times. Combine the Na25zOi extracts, wash once with 100 parts of ethyl acetate, combine the ethyl acetate extracts, and wash 3 times with 330 parts of H2O.
Washed twice. Combine the aqueous extract, 2001! Washed with 1 liter of ethyl acetate. Combine the ethyl acetate extracts again,
Washed with 300 mA brine, dried over Na, SO, filtered, and concentrated in vacuo to approximately 250 d.

The concentrate was then heated (in order to dissolve any solids that may be present), extracted with 50 IIIZ of isopropyl ether, and cooled. The title compound (Example 1b) crystallized spontaneously as fine white needles (29.6
g). Concentration of the mother liquor gave an additional 3.9 g of product. A portion of the first crop was recrystallized from ethyl acetate to obtain an analytical sample.

Melting point 157-158°C, spectral characteristics: 1r(CH
C13) 2980.1757.1670.1358.1
070 cm-'; nwr (CD CL) δ4.56 (
a+, IH), 3.97 (d, IJ 1=11.2,
8B IH) and 3°53 (d, IJ 1=11.2.1
8B H) [Center of pattern: 3, 75, Δ! '=19.7H
z] Eight B 3.50 3.90 (m, 2H), 2.30-2.7
0 (theory, IH), 1,80 2.30 (m,
3H), 1.73 (s, 3H);C
I3nmr (CDCIz) ppml 6 6.4.
164.3.85.4.58.3.45.5.37゜9
．． 29.9.24.7.21,8: [al = 1
31.4 (C=1.9745, CHC13).

Calculated value for 5iJLCs HI2B r N O-: C141°24; H, 4,62; N, 5.34. Actual value: cl 41.58: H, 4,78; N, 5.20
Example 1 (b) in 48% aqueous HBr at 160°
) of the title compound at 100-105°C.
The mixture was stirred in a bath for 16 hours and then cooled.

This solution was then poured into brine in 800d,
0mj! Extracted twice with CH and CI□. The combined organic extracts were washed with 300-820 ml of water and the aqueous layer was then extracted with three 500 LIll portions of ethyl acetate. The ethyl acetate extracts were combined and washed three times with 100II11 of brine and the resulting solution was dried over Na2SO4, filtered and evaporated in vacuo. Hot ethyl acetate/hexane (
1:4) to give 6.7 g of the title compound (Example 1c) as colorless rods and needles.

Concentration of the mother liquor and crystallization from a minimal amount of hot CHCl yields
A further 1.4 g of the title compound was obtained. Melting point 111.
5-114.0℃. Spectral characteristics: +r(CHCld3500 (br), 2970(br)
), 1722 (br), 1450.1182.108
108O section; nmr (CD C13) δ6.80, (v
, br, s, 2 H), 3°87 (d, IJ 1
= 10.4, IH) and 3.38 B 9 (d, IJ I = 10.4, IH) [B center into the pattern: 3.63, Δν = 21.7 Hzl, 1.62 (s
, 8B 3H); Cl nmr (CD C13) ppm 1
7 7. 9, 74.3.39.6.24.2;
[α165=-31,2 (C=1.

4, C'HC13); [α] = -10,9
(C=1.4, e l'F C4Ht B r O3
Calculated value: C, 26,25; H, 3,86° Actual value: C, 26,03; H, 3° 20mj! anhydrous TH
3.78 in F. A solution of the title compound of Example 1(c) was maintained under an inert atmosphere and cooled in a water bath. A 1M BH,.THF solution (65-) was added to this solution. The resulting reaction mixture was warmed to ambient temperature and stirred for approximately 20 hours. Add a small amount of THF to the reaction until H2 evolution stops.
It was stopped by adding a mixture of /H,O (1:1) followed by water. The mixture was then heated briefly, then cooled and extracted with three 25 ml portions of brine. The combined brine layers were extracted with 50 d of diethyl ether. The organic extracts were then combined and N a2SO-
dried, filtered and evaporated in vacuo. short bus (s)
(hort path) When vacuum distilled, approximately 3.3g
of the title compound (Example 1d) at 64°C (0°14 Torr). Spectral characteristics: 1r (CHCl=>3400 (
br), 2930.1460.1380.1042.8
90 e+a-': nmr (CD CIa) δ3,61
(d, lJ l=6.1, IH) 3°8B from t-J 53 (d, IJ I=6.1, IH) [B center into pattern: 3,60, Δν =6.7Hz ], 3.50 (s.

ΔB 2H), 2.75 (br, s, 2H) (OH-1 highly variable), 1. 3 1 (s, 3 H);C
I3nmr(CDC1,)ppm? 2,0.67°5.40.4.22.6; [']:+as=+10.7
2 (C=1.501, CHC13).

e l'r C-Hs B r Calculated value at O2: C, 28, 42; H, 5° 37° Actual value: C, 28,
42; H, 3.38 g of Example 1 (c
The solution of the title compound of l) was maintained at ambient temperature under an inert gas atmosphere. To this was added a catalytic amount of toluenesulfonic acid-hydrate and the resulting reaction mixture was stirred for about 15.5 hours, after which it was filtered through a plug of alumina and evaporated in vacuo.

Short-path distillation at atmospheric pressure gives 3.57 g of the title compound (Example 1e) as a colorless irritant liquid (boiling point 1
76-179° C., 760 Torr), which was very unstable to trace amounts of acid.

Spectral properties: ir (thin film) 2975.2860.1372.
1210.110011055cI11-';nmr(
DMSO-d') δ4,0? (d, IJ l=8.8
, IH) 8B and 3.62 (d, I J l =8.8, I
H) 8B [Center of pattern: 3.84, Δv = 20. IHz
], 8B 3.49M, 2H), 1.36(s, 3H) 1.34(
s.

3H), 1.31 (s, 3H); Cl5r++
sr(DMS O-d')pp import 109.6.79.7
．． 71.9.39.7.27゜1.26.6.23.2
;[α]zas=55.04(C=1.9075,
acetone): Rr=0.546 (7.

5% Et20, CH2Cl□).

A solution of 1.26 mol n-propylmethylam (prepared in diethyl ether from lithium wire and dry n-propyl bromide: 49, 7 ml) was maintained under an inert gas atmosphere and placed in a bath at -40°C. Cool with 2.
Treated with 85 g of CLICN (vacuum dried with P2O5). The resulting beige, nearly homogeneous cuprate solution was stirred at -40° C. for about 5 minutes, then transferred to a water bath and stirred for an additional 15 minutes. This solution was then combined with the title compound of Example 1e (2,1
(8 g) was added rapidly to a rapidly stirred solution (also maintained at approximately 0°C under an inert gas atmosphere). The resulting mixture was stirred at 0° C. for approximately 50 minutes and then incorporated into saturated aqueous NH<CI m made basic (pH 8.5-9.0) with aqueous NH,OH. The resulting immiscible test phase was separated and the aqueous phase was extracted three times with 125 + nl portions of diethyl ether. Combine the diethyl ether extracts and wash twice with 20 ml portions of brine;
Dry over M'g SO4, filter and evaporate in vacuo to give a colored oil. This substance is 1.9cm x 47゜5
Chromatography on a column of cm (%"×19') silica 5 del, eluting with 1.75% diethyl ether in CH2Cl□, isolated the main band (Rf = 0°34). An analytical sample was obtained by short-path distillation. Boiling point is approximately 130°C/7760 torr. Spectral properties: IR (thin film) 2930.2860.145
5.1370.1205.1055c+m″″’ :n
a+r(CD CIs) δ3,79(d.

IJ I=8.2, IH) and 3.63 (d.

ΔB IJ I=8.2, IH) [Center of pattern: 3.7
8B 1・Δ′8=7・5H・]・1・15−1・70(・
・6H), 1.39 (s, 3H), 1.38 (s, 3H)
), 1.26 (s, 3H), 0.90 (t% J=6.
3H); C1 nmr (CDCIs) ppml 0
9. 1, 81, 4, 74.

3.40.1.27.4.27.2.26.8.24゜9.23.3.14.0; [011g5= +6, 2
7 (C=1.2065, acetone).

(g) + The title compound of Example 1(f) in R-2-methyl-hexane-1,2-dio 300B was treated with 2N HC
It was treated with a solution of I/Tetrahydro7ran (1:1) for about 2.5 hours at ambient temperature. 20ml of this mixture
of diethyl ether and shaken vigorously. The immiscible phases were separated and the aqueous phase was extracted with three 15 ml portions of diethyl ether. The ether extracts were then combined;
Washed once with saturated aqueous sodium bicarbonate (10a+1) and prine (10wIl), dried over 7 um of sulfuric acid, filtered, and evaporated in vacuo to give the crude product (178+
g) was obtained. Kuge 7L, a-le
lror) Distillation (<0.1) gives the desired (+)
R-2-methyl-hexane-1,2-diol was obtained as a colorless viscous oil, which was distilled off at 40-90°C (pot temperature). This product is similar to the above Pappo.
) and the racemic 2-hydroxy-
(-)R, which is an acid split from 2-7 thiruhexanoic acid
The product was identical to that obtained by lithium aluminum hydride reduction of -2-hydroxy-2-methyl-hexanoic acid. (+)R-2-methyl- described in this example
Hexane-1,2-diol had the following spectral properties: 1r(CHC1i) 3380 (br), 29
40.2920.1460.1375.1030.89
0 c+n-';t+mr(CD C1,) δ3,4
3 (br, s, 2H), 2.57 (br.

s, 2H) (OH), 1,20 1.60 (m, 6H)
, 1.16 (s, 3H), 0.92 (t, J=6.3H
); C1connmr (CD Cl3)G19117 3
．． 1, 69.8, 38.

6%26,0,23.3.14.0 (one co-occurring band); [a] = +4.03 (C = 2.5795, C
HCIs): [α]5as=+12.54(C=2.5
795, CHCl3).

By utilizing a substantially similar procedure, the stereoisomer (-)S-2-methyl-hexane-1,2-diol is prepared as described in the following example.

Example 2 Preparation of (-)S-2-methyl-hexane-1,2-diol (a) N-methacroyl-D-proline D-proline (50 g) was dissolved in 430-20% aqueous sodium hydroxide. Dissolve and stir the resulting solution while cooling in a water bath while 217Ilj! of ether, then 4
00mj! 50 g of methacroyl chloride in ether were added dropwise over about 45 minutes. After another 30 minutes, the aqueous phase was removed and washed once with additional ether. The aqueous phase was then acidified with concentrated hydrochloric acid and extracted three times with ethyl acetate. These combined ethyl acetate extracts were vacuum distilled.

Crystallization of the resulting residue from a mixture of toluene and petroleum ether gives the title compound, N-methacroyl-D-proline, which is then recrystallized from acetate/petroleum ether to give 51,5° (53 %) of purified material was obtained.

51.5 g of the title compound of Example 2(a) were added to 722 ml
of dry dimethylformamide and maintained at ambient temperature under argon, while adding 100% of the reconstituted mixture to 1.
Stirred for 8 hours, then poured into 1900 Lolls of saturated aqueous sodium bicarbonate solution. The resulting mixture was extracted three times with ethyl acetate.

The combined extracts were washed twice with water, dried over sodium sulfate and evaporated in vacuo to remove the solvent. 170% residue
mj! of hot ethyl acetate and 120 ml of Improper Tools. Petroleum ether was added to the hot solution and then cooled to crystallize the product, which was filtered off and dried.

The yield was 21.5 g of the purified title compound of Example 2(f). Melting point 156-158°C. This is Example 1
(f) had identical ir and nn+r spectral properties to its enantiomer.

5g of the title compound of Example 2(f) and 50d of 48
16% aqueous hydrobromic acid to a bath temperature of 105°C.
Heated for an hour and then cooled. 50 m of the resulting mixture
j! Pour into saturated brine of 100 mI portions of WE
The extract obtained by extracting 41 R1 seedlings using an acid extractor was dried over magnesium sulfate, and then the solvent was removed by vacuum evaporation. Crystallization of the residue from ethyl acetate/hexane gave 237 g of the purified title compound of Example 2(c) as white needles: mp 108-111°C;
[α]D+io, i° (cl, 48, CHCI s )
, [α1,6°+28.7°(cl, 48, CHCl,
), nmr and ir are identical to the enantiomer of 1(c).

(d) -5-2-Methyl-hexane-1,2-diodi and following the procedure described in Examples 1(d) to 1(g), the compound (-)S-2-methyl-hexane-1, 2-diol and TR-7134 as described above.
can be used in the synthesis of

The present invention is characterized by (+)R-2-methyl-hexane-1,2-diol and (-)S-2-methyl-hexane-1,2-
Although a method for making diols has been described in detail, it should be recognized that similar procedures can be used to make similar substituted alkane-diols. Such a procedure is therefore considered equivalent to the claimed method of the present invention.

Patent Applicant Miles Laboratories Infusible

Claims (1)

[Claims] A method for producing 1,(+)R-2-methyl-hexane-1,2-diol, comprising: (a) reacting methacroyl chloride with L-proline in the presence of a base; , formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ to produce an amide, and (b) react the said amide with N-bromo-succinimide in an aprotic polar solvent to form the formula: ▲mathematical formulas, chemical formulas, tables, etc. (c) Hydrolyze the bromolactone with aqueous hydrobromic acid to produce a bromo acid with the formula: ▲Mathematical formula, chemical formula, table, etc.▼; ) reduction of said bromo acid with a mixture of borane-tetrahydrofuran to produce a bromo diol of the formula: (e) treatment of said bromo diol with dimethoxy-propane and toluenesulfonic acid; Then, formula: ▲mathematical formula, chemical formula,
(f) reacting said acetonide with dipropyl cuyuprate to produce an alkylated product of the formula: ) The alkylated product is reacted with acidic aqueous tetrahydrofuran to form (+)R-2-methyl-hexane-
A method characterized by producing 1,2-diol. 2. The method according to claim 1, wherein the base according to step (a) is sodium hydroxide. 3. The method according to claim 1, wherein the aprotic polar solvent according to step (b) is dimethylformamide. 4. A method for producing (-)S-2-methyl-hexane-1,2-diol, comprising: (a) reacting methachloride with D-proline in the presence of a base to produce the formula: ▲Math. , there are chemical formulas, tables, etc. ▼ to produce an amide, (b) the said amide is reacted with N-bromo-succinimide in an aprotic polar solvent to produce the formula: ▲ there are mathematical formulas, chemical formulas, tables, etc. ▼ (c) Hydrolyzing the bromolactone with aqueous hydrobromic acid to produce a bromo acid with the formula: Reduction with a mixture of borane-tetrahydrofuran to produce a bromodiol of the formula: ▲Mathematical formulas, chemical formulas,
(f) reacting said acetonide with dipropyl cuyuprate to produce an alkylated product of the formula: ) The alkylated product is reacted with acidic aqueous tetrahydrofuran to form (-)S-2-methyl-hexane-
A method characterized by producing 1,2-diol. 5. The method according to claim 4, wherein the base according to step (a) is sodium hydroxide. 6. The method according to claim 4, wherein the aprotic polar solvent according to step (b) is dimethylformamide.