JPS638091B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION Prostaglandins as a class have recently been the subject of intense research. Naturally occurring or synthesized prostaglandins are derivatives of prostanoic acids and are involved in a wide range of biochemical effects, including cardiac vascular, neurological, reproductive, renal, and gastric responses in animals. Pull it out. 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. The most active prostaglandin derivatives contain each asymmetric carbon atom and/or
or having a specific stereochemical configuration at the double bond is known in the art. 16-Methyl-1.11α.16RS-trihydroxypst-3E-en-9-one (e.g. TR-4698
No. 4,132,738 [issued January 2, 1979 to Kluender et al.] (this patent and other references cited therein are incorporated herein by reference). The prostaglandin analogs disclosed and claimed by (Added by). TR-4698 is a mixture of two isomers at the chiral C-16 position. This 16-R isomer (i.e., 16R-methyl 1, 11α, 16RS-trihydroxypst-
13E-en-9-one, hereinafter referred to as TR-7133)
is not believed to have the same degree of physiological activity as the 16-S isomer. However, the physiological activities that can be attributed to them upon reaction with those present in the racemic mixture or the 16-S isomer alone,
In order to evaluate the degree of toxicity, etc., it is desirable to be able to synthesize the 16-R isomer. This consideration may also be of value when satisfying the regulatory authorities involved in new drug approvals for physiologically active drugs. Therefore, we proposed the synthesis of an intermediate with the necessary stereochemistry that, when ultimately incorporated into this molecule, would provide only the 16-R isomer (TR-7133) rather than a racemic mixture. It has become desirable to release it. The method taught herein is that (+)R-2-methyl-hexane-1.
Concerning the synthesis of 2-diol (16-R isomer, intermediate for the preparation of TR-7133). The intermediate is prepared via an uncontrolled halolactonization 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 prostaglandin isomers. One such technique is to utilize resolved intermediates with the appropriate stereochemistry at the chiral center for incorporation into the molecule. For example, Pappo et al., Chemistry, Biochemistry and Pharmacological Activities of Prostanoids.
Biochemistry and Pharmacological Activity
of Prostanids,” edited by SM Roberts and F. Sheimann, pp. 17-26, Pergammon Press.
New York, 1978, teaches the resolution of racemic 2-hydroxy-2-methyl-hexanoic acid via its naphthylethylamine salt to produce chiral acetylenic alcohols.
(This optically active acetylenic alcohol can then be incorporated as the "right hand" portion of the prostaglandin analog according to known techniques). However, classical resolution of racemic 2-hydroxy-2-methyl-hexanoic acid is at best cumbersome and requires expensive optically active amines. Y. Fujimoto (Fujimoto), J. Yadev (Yadev)
Another approach taught by C. Sih, Tetrahedron Letters , 21, 1481 (1980) is (-)S-2-
Methyl-hexane-1,2-diol is prepared from (+) citramlic acid and then the chiral diol is used to prepare the corresponding optically active acetylenic alcohol. A disadvantage of this method is that isolated microbial enzymes must be used to produce citramaric acid from mesaconic acid. S-s. Jew, S. Terashima and K. Koda, Tetrahedron , 35, 2337 et seq. (1970)
and the papers cited therein describe optically active α·β-disubstituted-α-hydroxy acids as α·β-disubstituted-α-hydroxy acids.
It teaches the use of uncontrolled halolactonization reactions to prepare alpha-unsaturated acids. 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 acids in high optical purity. For example, Jew et al. found 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 higher than the S-isomer. They teach that they are produced in major ratios (approximately 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 (approximately 60:40, respectively). The generation described here is (+)R-2-methyl-hexane-1.2 from methacroyl chloride.
- Teach the production of diols. As mentioned above, this intermediate is the optically active component of prostaglandins.
16-R, such as TR-7133. The present invention relates to the products of the stereospecific prostaglandin intermediate (+)R-2-methyl-hexane-1,2-diol. This method involves reacting methacroyl chloride with L-proline in the presence of a base to give the formula The step of producing an amide of This amide was then reacted with N-bromo-succinimide in an aprotic polar solvent to form the formula of bromolactone. This bromolactone is then hydrolyzed with aqueous hydrobromic acid to give the formula of bromo acid. The bromo acid was then reduced with a borane-tetrahydrofuran mixture to give the formula of bromodiol. This bromodiol was then treated with dimethoxy-propane and toluenesulfonic acid to give the formula of acetonide. This acetonide is then reacted with dipropyl cuyuprate to give the formula of the alkylated product. This alkylated product is then reacted with acidic aqueous tetrahydrofuran to form (+)R-2-methyl-hexane-
1,2-diol is produced. The method 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-methacroyl-L was prepared by adding methacroyl chloride dropwise to an aqueous mixture of L-proline, sodium bicarbonate and diethyl ether.
- Proline is prepared first (PH is approx. 10 throughout)
-11) and stir the mixture at ambient temperature for about 15 minutes to about 2 hours (Step A). N-methacroyl-L-proline is then isolated according to conventional extraction techniques. Bromolactonization is then carried out as follows. N-bromosuccinimide (NBS) is added to the above L-proline derivative in an aprotic solvent, e.g. dimethylformamide (DMF), and then at ambient temperature
Stir for 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 dissolved in tetrahydrofuran.
Reduction by treatment with a mixture of BH ₃ (step D). This mixture is heated at ambient temperature from about 12 to about 24
Stir for an hour and then stop the reaction by adding a small amount of a mixture of tetrahydrofuran/water (approximately 1:1). The resulting bromodiol is then recovered by conventional techniques as described below. This bromophenol is converted into dimethoxypropane (DMP)
and a catalytic amount of toluenesulfonic acid at ambient temperature with agitation for about 8 to about 24 hours, thereby protecting the bromodiol 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. See BH Lipshutz et al., Journal of American Chemical Society ( J.Am.Chem.Soc. ), 103 , 7672 (1981).
The resulting cuprate solution is added to a solution of the above acetonide 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. The stirred mixture is then poured into a saturated aqueous ammonium chloride solution (PH about 8-9) and shaken. The resulting alkylated product is recovered by conventional means and then treated with acidic aqueous tetrahydrofuran (Step G) to yield the desired (+)R-2-methyl-hexane-1,2-diol. (+)R-2- produced by the method of the present invention
Methyl-hexane-1,2-diol can be utilized in the production of certain stereospecific prostaglandin analogs (according to known techniques), 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.
It can be used to prepare 4-methyloct-1-yn-4R-ol. The reaction order is shown in Table 2. As shown in Table 2, (+)R-2-methyl-hexane-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 fluoride (KF) in dimethylformamide
treatment and purification yields the desired stereospecific acetylenic alcohol, 4-methyloct-1-
In-4R-ol is obtained. Kluender et al. (U.S. Patent No.
No. 4132738, cited above) teaches,
The above acetylenic alcohol is then converted to the corresponding iodovinyl alcohol. 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). The hydroxy-protected iodovinyl alcohol is then lithiated with t-butyllithium and reacted with a complex of solubilizing ligands of copper() compounds, such as (hexamethylphosphorustriamide) ₂ -copper()pentyne. Generates organolithioucparate. Then, this organolithioparate was converted into 4R-(tetrahydropyran-2-yloxy)
Reaction with -2-[7-tetrahydropyran-2-yloxy)heptyl]-2-cyclopent-2 enone produces the tetrahydropyran protected form of TR-7133. The protected form is then hydrolyzed with a weak acid to produce TR-7133. As can be seen, the optically active (+)R-2-methyl-hexane-1.2
- Diols can be used to produce other prostaglandin analogs. The invention is illustrated by the following examples. Example 1 Preparation of (+)R-2-methyl-hexane-1,2-diol (a) N-methacroyl-L-proline L-proline (42.0 g), NaHCO ₃ (148 g),
A mechanically stirred mixture of _H2O (680ml) and diethyl ether was brought to PH in a bath at ambient temperature.
10.5-10.7 (adjusted by addition of concentrated aqueous NaOH) then diethyl ether (20ml)
redistilled methacroyl chloride (40
ml) solution in portions over 20 minutes. Add additional concentrated aqueous NaOH as needed to adjust the pH.
Maintained at 10.5-10.7. When all the methacroyl chloride had been added (and the PH had stabilized), the mixture was stirred at ambient temperature for 20 minutes. The resulting unsaturated phase was separated and the aqueous phase was extracted with two 250 ml portions of diethyl ether. Combined organic extracts in H ₂ O (50 ml)
and the aqueous extract was added to the aqueous phase, this phase was then acidified to PH1 with concentrated aqueous HCl and then
Extracted with four 250 ml portions of ethyl acetate. The combined ethyl acetate extracts were washed with approximately 100 ml of brine (saturated aqueous sodium chloride solution) and
It was then dried with Na ₂ SO ₄ . The resulting solution is filtered and concentrated in vacuo to approximately 230 ml, 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 columns (51.3 g). A portion of the first crop was recrystallized twice from ethyl acetate to obtain a sample for analysis. Melting point 102-104.5℃. Spectral characteristics: ir
( _CHCl3 ) 2970, 1712, 1610, 1455, 1440,
1200, 915cm ^-1 ; nmr (CDCl ₃ ) δ11.7 (s, 1H),
5.05−5.40 (m, 2H), 4.60 (t, J=6, 1H),
3.64 (t, J=6, 2H), 1.90−2.50 (m, 4H),
1.96 (s, 3H); C ¹³ nmr (CDCl ₃ ) ppm 174.7,
171.9, 140.5, 117.5, 59.1, 49.5, 28.9, 25.0,
19.6; [α] _D = -136.41 (C = 1.111, CHCl ₃ ),
Optical rotation changes with concentration. Calculated values for analysis C ₉ H ₁₃ NO ₃ : C,
59.00; H, 7.15; N, 7.65. Actual value: C,
58.90; H, 6.99; N, 7.67. (b) 3S-bromomethyl-3-methyl-1,4-
Dioxo-3.4.6.7.8.8αS-hexahydro-1H-pyrrolo[2.1-c][1.4]
Oxazine 36.6 g of the title compound of Example 1(a) were added to 500 ml of dry (4 Å) dimethylformamide, maintained at ambient temperature under an atmosphere of inert gas (protected from light) and recrystallized with N. - treated with bromosuccinimide (71.2 g). The resulting mixture was stirred for about 20 hours and then mixed with saturated aqueous sodium bicarbonate (2) and ethyl acetate (800
ml) and shaken vigorously. The resulting immiscible phase is separated and the aqueous phase is
Extracted with three ml portions of ethyl acetate. Saturate 125 ml portions of the combined ethyl acetate extracts.
Extracted 8 times with Na ₂ S ₂ O ₃ . Combine the Na ₂ S ₂ O ₃ extracts and wash once with a 100 ml portion of ethyl acetate.
The ethyl acetate extracts were combined and washed three times with 330 ml portions of _H2O . The aqueous extracts were combined and washed with 200ml of ethyl acetate. The ethyl acetate extracts were recombined, washed with 300 ml of brine, dried over Na ₂ SO ₄ , filtered and ca.
It was concentrated in vacuo to 250ml. The concentrate was then heated (to dissolve any solids that may be present) and extracted with 50 ml of isopropyl ether.
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℃. Spectral properties: ir( _CHCl3 )
2980, 1757, 1670, 1358, 1070cm ^-1 ;nmr
(CDCl ₃ ) δ4.56 (m, 1H), 3.97 (d, |J _AB |=
11.2, 1H) and 3.53 (d, | J _AB | = 11.2, 1H)
[Pattern center: 3.75, Δν _AB = 19.7Hz] 3.50−
3.90 (m, 2H), 2.30−2.70 (m, 1H), 1.80−
2.30 (m, 3H), 1.73 (s, 3H); C ¹³ nmr (DCl ₃ )
ppm166.4, 164.3, 85.4, 58.3, 45.5, 37.9,
29.9, 24.7, 21.8; [α] _D = -131.4 (C = 1.9745,
_CHCl3 ). Calculated values for analysis C ₉ H ₁₂ BrNO ₃ : C,
41.24; H, 4.62; N, 5.34. Actual value: C,
41.58; H, 4.78; N, 5.20. (c) (-)S-2-hydroxy-2-methyl-3
-Bromo-propionic acid A solution of 13.0 g of the title compound of Example 1(b) in 160 ml of 48% aqueous HBr in a bath at 100-105°C.
Stir for 16 hours, then cool. This solution was then poured into brine in 800 ml and extracted with two 500 ml portions of CH ₂ Cl ₂ . The combined organic extracts were washed with 300 ml of _H2O , then the aqueous layer was
Extracted three times with 500 ml portions of ethyl acetate. The ethyl acetate extracts were combined and washed three times with 100ml brine and the resulting solution was dried over Na ₂ SO ₄ , filtered and evaporated in vacuo. hot ethyl acetate/
When crystallized from hexane (1:4), 6.7 g
The title compound (Example 1c) was obtained as colorless rods and needles. Concentration of the mother liquor and crystallization from a minimum amount of hot CHCl ₃ gave an additional 1.4 g of the title compound. Melting point 111.5-114.0℃.
Spectral characteristics: ir ( _CHCl3 ) 3500 (br), 2970
(br), 1722 (br), 1450, 1182, 1080cm ^-1 ; nmr
(CDCl ₃ ) δ6.80 (v.br.s, 2H), 3.87 (d, ｜J _AB ｜
= 10.4, 1H) and 3.39 (d, | J _AB | = 10.4,
1H) [Pattern center: 3.63, Δν _AB = 21.7Hz],
1.62 (s, 3H); C ¹³ nmr (CDCl ₃ ) ppm 177.9,
74.3, 39.6, 24.2; [α] ₃₆₅ = -31.2 (C = 1.4,
CHCl ₃ ); [α] _D = −10.9 (C = 1.4, CHCl ₃ ). Calculated values for analysis C ₄ H ₇ BrO ₃ : C,
26.25; H, 3.86. Actual value: C, 26.03; H,
3.89. (d) (+)R-2-Methyl-3-bromo-propene-1,2-diol A solution of 3.78 g of the title compound of Example 1(c) in 20 ml of anhydrous THF was prepared under an inert atmosphere. and cooled in an ice bath. This solution contains 1 mol of
_BH3.THF solution (65ml) was added. The resulting reaction mixture was warmed to ambient temperature and stirred for approximately 20 hours. Add a small amount of H2 to the reaction until the evolution of _H2 stops.
It was stopped by adding a mixture of THF/H ₂ 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 50ml diethyl ether. The organic extracts were then combined, dried over Na ₂ SO ₄ and
filtered and evaporated in vacuo. short pass
After vacuum distillation, approximately 3.3 g of the title compound (Example 1d) were obtained as a colorless viscous syrup. Boiling point 63-64°C (0.14 Torr). Spectral properties: ir( _CHCl3 ) 3400(br), 2930,
1460, 1380, 1042, 890cm ^-1 ; nmr ( _CDCl3 )
δ3.61 (d, | J _AB | = 6.2, 1H) and 3.53 (d, |
J _AB | = 6.1, 1H) [Center of pattern: 3.60,
Δν _AB =6.7Hz], 3.50 (s, 2H), 2.75 (br.s, 2H)
( OH , highly variable), 1.31 (s, 3H); C ¹³ nmr
(CDCl ₃ ) ppm72.0, 67.5, 40.4, 22.6; [α] ₃₆₅
=+10.72 (C=1.501, _CHCl3 ). Calculated values for analysis C ₄ H ₉ BrO ₃ : C,
28.42; H, 5.37. Actual value: C, 28.42; H,
5.18. (e) (-)S-1,1-Dimethyl-4-bromomethyl-4-methyl-2,3-dioxolane Example 1 of 3.38 g in acetone (50 ml) and freshly distilled dimethoxypropane (3.0) ml A solution of the title compound of (d) was maintained at ambient temperature under an inert gas atmosphere. To this was added a catalytic amount of toluenesulfonic acid monohydrate and the resulting reaction mixture was stirred for about 15.5 hours, after which it was passed through a plug of alumina and evaporated in vacuo. Shot pass distillation at atmospheric pressure gave 3.57 g of the title compound (Example 1e) as a colorless, pungent liquid (boiling point 176-179°C, 760 torr), which is highly unstable to trace acids. It was hot. Spectral characteristics: IR (thin film) 2975,
2860, 1372, 1210, 1100, 1055cm ^-1 ;nmr
(DMSO−d ⁶ ) δ 4.07 (d, | J _AB | = 8.8, 1H) and 3.62 (d, | J _AB | = 8.8, 1H) [center of pattern: 3.84, Δν _AB = 20.1 Hz], 3.49 M, 2H),
1.36 (s, 3H) 1.34 (s, 3H), 1.31 (s, 3H);
C ¹³ nmr (DMSO−d ⁶ ) ppm 109.6, 79.7, 71.9,
39.7, 27.1, 26.6, 23.2; [α] ₃₆₅ = −55.04 (C =
1.9075, acetone); R _f = 0.546 (7.5% _Et2O ,
_{CH2Cl2 )} . (f) (+)R-1,1-dimethyl-4-(n-butyl)-4-methyl-1,3-dioxolane A solution of 1.26 mol n-propylmethium (lithium wire and dry n-propyl bromide) (49.7 ml) maintained under an inert gas atmosphere, cooled in a bath at -40<0>C and treated with 2.85 g of CuCN (dried in vacuo over _P2O5 ) _. The resulting beige-colored, nearly homogeneous cuprate solution was stirred at -40°C for approximately 5 minutes, then transferred to an ice bath and stirred for an additional 15 minutes. This solution was then added rapidly to a rapidly stirred solution of the title compound of Example 1e (2.18 g) in 10 ml of diethyl ether, also maintained at about 0° C. under an inert gas atmosphere. . The resulting mixture was stirred at 0<0>C for approximately 50 minutes and then formulated into a saturated aqueous _NH4Cl solution made basic (PH8.5-9.0) with concentrated aqueous _NH4OH . The resulting immiscible phases were separated and the aqueous phase was extracted with three 125 ml portions of diethyl ether. The diethyl ether extracts were combined, washed twice with 20 ml portions of brine, dried over _MgSO4 , filtered,
Evaporation in vacuo gave approximately 1.2 g of the title compound (Example 1f) as a pale yellow oil. This material was chromatographed on a 1.9 cm x 47.5 cm (3/4" x 19") column of silica 5 gel and CH ₂ Cl ₂
The main band (R _f =0.34) was isolated by elution with 1.75% diethyl ether. Analytical samples were obtained by rapid shot pass distillation. Almost boiling point
130℃/776 Torr. Spectral characteristics: IR (thin film) 2930, 2860, 1455, 1370, 1205, 1055
cm ^-1 ; nmr (CDCl ₃ ) δ3.79 (d, | J _AB | = 8.2,
1H) and 3.63 (d, |J _AB | = 8.2, 1H) [center of pattern: 3.71, Δν _AB = 7.5Hz], 1.15−1.70
(m, 6H), 1.39 (s, 3H), 1.38 (s, 3H),
1.26 (s, 3H), 0.90 (t, J=6, 3H);
^C13 nmr ( _CDCl3 ) ppm109.1, 81.4, 74.3, 40.1,
27.4, 27.2, 26.8, 24.9, 23.3, 14.0; [α] ₃₆₅ =
+6.27 (C=1.2065, acetone). (g) (+)R-2-methyl-hexane-1,2-
Diol 300 mg of the title compound of Example 1(f) was dissolved in 2N
Treated with a solution of HCl/tetrahydrofuran (1:1) for about 2.5 hours at ambient temperature. The mixture was diluted with 20 ml of diethyl ether and shaken vigorously. Separate the immiscible phase and separate the aqueous phase at 15
Extracted with three ml portions of diethyl ether.
The ethereal extracts were then combined with saturated aqueous sodium bicarbonate (10ml) and brine (10ml).
The crude product (178 mg) was obtained after washing once with sodium sulfate, drying over sodium sulfate, filtration and evaporation in vacuo. Kugelror distillation (<0.1 torr) affords the desired (+)R-2-methyl-hexane-1,2-diol as a colorless viscous oil, which varies from 40 to 90 °C (pot temperature ) was distilled off. This product is an acid (-)R-2-hydroxy- resolved from racemic 2-hydroxy-2-methyl-hexanoic acid as described by Pappo et al., supra.
The product was identical to that obtained by lithium aluminum hydride reduction of 2-methyl-hexanoic acid. The (+)R-2-methyl-hexane-1,2-diol described in this example had the following spectral properties: ir( _CHCl3 )3380(br),
2940, 2920, 1460, 1375, 1030, ^{890cm -1} ;
nmr ( _CDCl3 ) δ3.43 (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); C ¹³ nmr
(CDCl ₃ ) ppm73.1, 69.8, 38.6, 26.0, 23.3,
14.0 (one simultaneous band); [α] _D = +4.03
(C = 2.5795, CHCl ₃ ); [α] ₃₆₅ = +12.54 (C =
2.5795, _CHCl3 ). By utilizing substantially similar procedures,
Stereoisomer (-)S-2-methyl-hexane-
The 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 ml of 20% aqueous sodium hydroxide. and stir the resulting solution while cooling in an ice bath, while adding 217 ml of ether followed by 50 ml of ether in 400 ml of ether.
g of methacroyl chloride was 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 yields the title compound N
-Methacroyl-D-proline was obtained which was then recrystallized from acetone/petroleum ether to yield 51.5 g (53%) of purified material. (b) 3R-bromomethyl-3-methyl-1,4-
Dioxo-3,4,6,7,8,8αR-hexahydro-1H-pyrrolo[2,1-c][1,4]
Oxazine 51.5 g of the title compound of Example 2(a) are added to 722 ml of dry dimethylformamide and maintained at ambient temperature under argon while 100 g of recrystallized N-bromosuccinimide are added. The resulting mixture was stirred for 18 hours and then poured into 1900 ml 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. Pour the residue into 170 ml of hot ethyl acetate and 120 ml of hot ethyl acetate.
ml of isopropanol. 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
℃. This is the same ir as its enantiomer in Example 1(f).
and nmr spectral characteristics. (c) (+)R-2-hydroxy-2-methyl-3
- Bromopropionic acid 5 g of the title compound of Example 2(f) and 50 ml of
A mixture of 48% aqueous hydrobromic acid was heated to a bath temperature of 105° C. for 16 hours and then cooled. Pour the resulting mixture into 50ml of saturated brine and add 100ml
This portion was extracted four times with ethyl acetate. The combined extracts were dried over magnesium sulfate and then evaporated in vacuo to remove the solvent. Crystallization of the residue from ethyl acetate/hexane gave 2.7 g of the purified title compound of Example 2(c) as white needles: mp 108-111 °C, [α] _D +
10.1゜(c1.48, CHCl ₃ ), [α] ₃₆₅ = +28.7゜(c1.48
,
CHCl ₃ ), nmr and ir are the same as the enantiomer of 1(c). (d) (-)S-2-methyl-hexane-1,2-
Diol Following the procedure described in Examples 1(d) to 1(g),
Compound (-)S-2-methyl-hexane-1.
The 2-diol can be prepared and used in the synthesis of TR-7134 as described above. The present invention is (+)R-2-methyl-hexane-
Although we have detailed the preparation of 1,2-diol and (-)S-2-methyl-hexane-1,2-diol, it should be recognized that similar procedures can be used to prepare similar substituted alkane-diols. It is. Such a procedure is therefore considered equivalent to the claimed method of the present invention.

Claims (1)

[Claims] 1 (+)R-2-methyl-hexane-1,2-
A method for producing a diol, the method comprising: (a) reacting methacroyl chloride with L-proline in the presence of a base to obtain the formula: (b) reacting said amide with N-bromo-succinimide in an aprotic polar solvent to form an amide of the formula: (c) hydrolyzing said bromolactone with aqueous hydrobromic acid to produce a bromolactone of the formula: (d) reducing said bromo acid with a mixture of borane-tetrahydrofuran to produce a bromo acid of the formula: (e) treating said bromodiol with dimethoxy-propane and toluenesulfonic acid to produce a bromodiol of the formula: (f) reacting said acetonide with dipropyl curate to form an acetonide of the formula: and (g) reacting said alkylated product with acidic aqueous tetrahydrofuran to produce (+)R-2-methyl-hexane-1,2-diol. How to do it. 2. The method of 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 (-)S-2-methyl-hexane-1,2-
A method for producing a diol, the method comprising: (a) reacting methacroyl chloride with D-proline in the presence of a base to obtain the formula: (b) reacting said amide with N-bromo-succinimide in an aprotic polar solvent to form an amide of the formula: (c) hydrolyzing said bromolactone with aqueous hydrobromic acid to produce a bromo acid of the formula: (d) reducing said bromo acid with a mixture of borane-tetrahydrofuran to produce a bromo acid of the formula: (e) treating said bromodiol with dimethoxy-propane and toluenesulfonic acid to produce a bromodiol of the formula: (f) reacting said acetonide with dipropyl curate to form an acetonide of the formula: and (g) reacting said alkylated product with acidic aqueous tetrahydrofuran to produce (-)S-2-methyl-hexane-1,2-diol. How to do it. 5. The method of claim 4, wherein the base according to step (a) is sodium hydroxide. 6. The method of claim 4, wherein the aprotic polar solvent according to step (b) is dimethylformamide.