JPS58170725A - Glycerol derivative - Google Patents

Abstract

NEW MATERIAL:An L-threitol derivative or D-threitol derivative expressed by formula I (R<1> is 8-22C hydrocarbon residue or benzyl) or formula II (both R<2> and R<3> are lower alkyl or R<2> is H and R<3> is phenyl or cyclohexyl or R<2> and R<3> form a cyclohexyl ring or cyclic acetal type protecting group of the diol). EXAMPLE:1-O-Hexadecyl-2-O-benzyl-L-threitol. USE:A raw material for hypotensive agents, antitumor agents, etc. PROCESS:A compound expressed by formula IV is reduced with lithium aluminum hydride and aluminum chloride to give a compound expressed by formula V. The 1,2-diol of the resultant compound expressed by formula V is then protected to afford a compound expressed by formula VI, which is then debenzylated to give a compound expressed by formula II. On the other hand, the compound expressed by formula VI is reacted with NaOH to give a compound expressed by formula VII, which is further reacted with a compound expressed by the formula R<1>-X (X is halogen, etc.) to afford the compound expressed by formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention describes optically active precursors of D- or L-glyceraldehyde P conductors having the general formula EC) and KIAI (wherein R
1 indicates a linear or branched hydrocarbon residue having 8 to 22 carbon atoms or a benzyl group, R" and R" are both RN and Rm lower alkyl groups, or R3 is a water atom and R3 is phenyl group or Schiff q is a syl group, or R2 and R
3 forms a cyclohexyl ring to form a cyclic acetal group of diol. ) Each optical activity represented by the compound (D-form and L-form)
The compounds represented by the general formulas [I6] and (1b) are subjected to 1,2-diol oxidation conditions to form the general formula [I6] and (1b).
[Otori] and [Seiben] [18] [Cao b] (in the formula, R
1, R1 and R3 have the same meanings as above. ), and then by reducing the aldehyde group, a D- or L-dalicelaldehyde derivative represented by
and [Zenk] [厘-3CIA) (In the formula, Hl, R2, and BS have the same meanings as above.)
How to obtain a D- or L-glycerin derivative represented by f
It is kW14.

Conventionally, to obtain zero D-dalicelaldehyde, there is a method using D-mannitol or D-fructose as raw materials [Journal Ono] ZIlogical Science Story, Shisho, 46
3 (1939), Methods in Carbohydrate Chemistry, 1.61. (1962)] is known, and L-glyceraldehyde can be used as L-sorbose or a nitrogen-containing N material [Method in Carbohydrate Chemistry, 1.61. (1962
), Journal of the American Chemical Society, 102', "6304 (19801)]. However, a method for producing glycerin derivatives from -6 acid has not yet been developed.

The present invention provides optically active L-(+1-1i taric acid or D-(-
)-tartaric acid as a raw material compound, the general formula [C] and (1
! A method for producing L-threitol derivatives and D-threitol derivatives represented by the following formulas:
One optical isomer (L or D) from 1 m taric acid.

This provides a useful method for producing any desired L- or D-glycerin derivative, and the resulting glycerin derivative is extremely useful as a raw material compound for useful physiologically active substances, as described below. It is rich.

According to the present invention, the compounds represented by the general formulas [18) and [1h] are known compounds obtained from a di-alkyl ester of L-(+l-tartaric acid or D-(-1-tartaric acid) and penzaldehyde. The metal compound represented by the general formula [IV] (wherein R is a lower alkyl group) is used as a starting material and can be obtained by the reaction process shown below. 〔■〕 〔■〕 Inert am1 compound represented by the general formula OV), such as ether, tetrahydro7rane, methylene chloride, chloroform-sulfur, lithium aluminum hydride in toluene at the reflux temperature of the solvent under water cooling. By reducing K with aluminum chloride, triolized metal (Vl
is obtained.

The triol [■] is then subjected to a reaction to preserve the 1,2-diol as a tm-like acetal, resulting in a metal compound represented by the general formula [■].

In the general formula [VI], Hm, Hm is a tar type protective group,
, notylidene, indyl, lydene, cyclobendi 9-f7
, cyclohexylidene group. In an inert solvent such as inzentoluene, tetrahydrofuran, dioxane, the corresponding aldehyde, ketone, 2,2-dimethoxy7
Obtained by conventional reaction conditions with pro/(.

1! , HI3 The above-mentioned thin cyclic aceter) Extract 10 > Hei 3 General formula [1] The compound represented by the formula (Vl) may be debenlated. The debenzylation reaction can be easily carried out by catalytic reduction using commonly used reducing catalysts such as noridium-carbon, palladium black, Raney nickel, and platinum oxide. In addition, in the general formula [1tL), R1 is a hydrocarbon bulk residue having 8 to 22 carbon atoms, or a benzyl group, which is a compound of the formula [■]. #Rope, such as benzene, toluene,
In a solvent such as tetrahydro7rane or dimethylformamide, il! from sodium hydroxide or potassium hydroxide and il! The reaction is carried out at the reflux temperature of #&, and then the general formula 1 R1-X
or a sulfonylambdaoxy group substituted with a methyl, 7enyl or tolyl group. ) in the reaction solution, add with cooling if necessary, add OC
The compound is reacted at the reflux temperature of the solvent to obtain a compound represented by the general formula [button], and then subjected to a deacetal reaction. This deacetalization reaction can be carried out under commonly used conditions, and is carried out using an acid in a water-containing solvent such as methanol, ethanol, or tetrahydrofuran.

The metal compounds represented by the general formulas [1m] and (14) can be obtained by oxidizing the 1,2-diol of the metal compounds represented by the general formulas (1-1 and (163) to form an aldehyl r group. As this oxidizing agent, lead tetranolate, sodium periodate, etc. are suitably used.

Examples of solvents that can be used include benzene, toluene, ether, tetrahydrofuran, dioxane, methylene chloride, chloroform, etc. when oxidizing with lead tetranolate, and when oxidizing with sodium periodate. , methanol, ethanol, etc.゛By reacting from 01' in these ams at the reflux temperature of the solvent, the chemical formulas expressed by the formulas [Otori a] and [Rinshaku] are obtained. The aldehyde 1 compound that is used is often unstable and difficult to isolate; in such cases, the oxidation reaction of the diol is carried out, followed by reduction of the aldehyde compound to form the general formula [ It is necessary to extract it as an alcohol represented by sulfur a) and [lh].

It goes without saying that the metal compounds included in the reaction of the present invention each contain an optical antipode.

From the compounds represented by the formulas [1-] and [Ih], 5 or 0 Daliserisi trout derivatives can be obtained by a known reaction, respectively.
You get a body. -L-(+l-tartaric acid) is used as the first raw material, for example, if it is threatened by a chemical compound such as platelet activating factor (PAF), which will be described later, with the formula cio and R1 being 08 to 022, it may contain non-natural tartaric acid (anti-tartaric acid). Port 9) is obtained, and a compound in which R1 is a benzyl group or an acetal compound of formula [181] can be synthesized from a natural store.Also, D-(-)-tartaric acid This and its optical enantiomer compounds can be obtained from the glycerin molded conductor obtained, which can lead to compounds of physiological interest.

It can be understood from the following that it is an extremely useful compound.

Platelet activating factor (pla%@1・%@*c%Lva%
Shifac%or.

Hereinafter abbreviated as PAF. ) [Nature, 258, 193. (1980) (1980) (in the formula, ro represents 15 and 17) has also been shown to have a very strong hypotensive effect. PAF is one of the immunostimulatory factors in humans, and is further thought to be one of the causative substances of allergic reactions and inflammatory reactions. Do you obey? Compounds that extract PAFK (inhibit the action of PAF) have great potential to become unprecedented Kosaka aggregation inhibitors, anti-allergic agents, or anti-inflammatory agents, and from this perspective, compounds that antagonize PAFK, Dalycerylphosphorylcholine trout conductor has been discovered←Special request! M-48368 reference M1), and compounds that have almost no platelet aggregation effect and have only a blood pressure lowering effect, focusing on the antihypertensive effect of PAF, can be used as raw material compounds for these compounds.

In addition, 1-0-furkylglycerylphosphorylpurine derivatives have been shown to inhibit the growth of tumor cells and, as an antitumor agent, to prolong the survival of leukemia and solid cancer [Unexamined Japanese Patent Publication Wi85]
6-120690. and Ca/Sar Research, Dan, 32
11 (1981)].

Arachitonanoic acid liberated by the action of phosphorase produces the Kokosaka aggregation factor thrombokinane A2 ('rx*
It is known that leukotriene substances (fsR8-me) are generated in the phosphoryl and leukotriene substances (fsR8-me). Therefore, the 11111F agent of phospho-Vj-ase, which provides free vclI of arachidonic acid, inhibits platelet aggregation and allergic reactions.

Glycerin conductors having such a phosphorylase inhibitory effect are known (Biochim, Bio
phya.

Mucta, 164, 226. (194S8) #
Irradiation can also serve as a raw material for the synthesis of such compounds. Furthermore, it goes without saying that these glycerin cast conductors are not only natural types but also anti-boards as physiologically active substances.

Next, examples and reference examples of the present invention will be given for 1 mH.

Reference example 1 I of 2-o-indyl-L-threitol! Under a stream of argon, 91 tons of lithium aluminum hydride (1
24 mol) was suspended in 100-mol of dehydrated ether and 50-mol of methylenetalolide.

Under water cooling, 2-(R)-3(R)-2,5-0-indicidene 1lIi tartaric acid dimethyl ester (synthesized from L-(◆)-acetate) 1(1(37,6-ken Limo J&I) was dissolved in dry methylene coolide (80wJK), stirred for 30 minutes at C30C, and further stirred for KsO.Next, 200dK of aluminum chloride (5'L9tCα24 mol)k ether was dissolved at Kli temperature, sieved for 50 minutes, and then heated under reflux for 1 hour. Cooled and poured 500% of tetrahydrofuran.
9J1, and then added water 18- over 30 minutes.
15 After diluting 100 m of sei soda aqueous solution and 54 m of water, it was filtered, washed with 307 runs of tetrahydrochloride, and the washing solution and F moat were combined, dehydrated and condensed to yield 7.81 t (98 m) of the target compound.
(sound) was obtained.

Peng? Near 3~76C0 [α] 2”x+t5.7@(O1Oot methanol).

NMR ((aj,): J = lS ~3.6(11
, 4H), 3,6-5.9 (++a, 511), 4
46(j, 11.J=121iz), 443(j, I
M, J=12Hz), 7.27C1,511).

IjL (KBr): F=53QOs 1450C1l
chMUl@:m/g=212CM), 181,1
63,151゜〒LC (ethyl i11 acid 1: benzene y1
):la/=a15(ethyl acetate 1:methanol 1)S
R/-185°, Reference example 2 2-0-indyl-3,4-0-inozolobylidene-L
-Production of slate- 2,2-dimethoxyproA 780 caps (7,5 < 9 caps) obtained in Reference Example 1 was placed in a vacuum vessel equipped with a Soxhlet extraction tube containing 4 mm of molecular sheep and 2 tons of molecular sheep. Compound 'L0
The mixture was added to a catalytic amount of 6tC5<9 mo#), water, garlic, and a catalytic amount of 71-) and heated under reflux for 1 hour. Cool the 1llillK and add 1sJk of triethylamine? 1011 was distilled off under reduced pressure.

With the only remaining silica gel column taromadogutufi [11
The target compound 1262 (yield: 100) was obtained as a colorless oil (by extraction with a solvent of 1 part ethyl and 1 part benzene).

[α) Dx-1685' (OL51@Ku W book) A).

s NMR (ODOj, ): J-158 (#, 511)
,'L44C1,511).

2.24(selH)-114-48(,3H), 1g
? (di.

11, Jz7Hm, 8Hs), to I Cdd,
111. Jx7Hz.

811s), 428(v-Ill, J-6Hs)
, 472 (s, 1 sweetfish 4.74 (#, IH), 7.3
3(#, 51().

IR (moat law) Niji = 5460.2900.2B60.
1380°I SS70t.

Mhaa: V′m=252 CM”), 257
, 221° Reference Example 3' 1-0-hequinadecyl-2-0-indyl-44-0-
Production of isopropylidene-threitol Under argon atmosphere, metal compound 252M9 (1 V mol) obtained in Reference Example 2
An oil suspension of water-volumized potassium in a solution of 10- toluene (approximately 100 If
, α25 mm) was added slowly. After the generation of water bulges has stopped, stir for another 50 minutes and add to the mixture.
The mixture was added to toluene and heated under reflux for about 10 hours. After cooling, 71 M of hequinane, 1:1 of ethanol and 1:1 of water were added to the reaction solution, extracted with ethyl acetate, and the organic layer was dehydrated and collected. ! The target metal was eluted with benzene, then ethyl acetate, and then ethyl acetate to give a white powder of 415 dah (porosity: 87 g).

111 (KBy):y=3450.2920.286
0, 1455゜1M70m-1゜-(18 Mass. 2 father-in-law/a = 474 (M”), 4
61. 418゜DLO (ba/in) SR/=α56゜Reference example 4 Production of 2-0-benzyl-D-threitol D-(-1
--By the same method as described in Reference Example 1, using a compound obtained from soap and having the general formula 'Bf methyl, 9? Obtained in poor yield.

Reference f15 2-0- to Fujiru 44-0-isozolobylidene-D-
Production of threitol Quantitative KII made from the metal compound obtained in Reference Example 4 by the same method as described in Reference Example 2.

Reference example 6 1-0-hequinadecyl-2-0-indyl-44-〇-
Production of Inozolobidadene-D-Threitol was obtained from the metal compound obtained in Reference Example 5 by the method described in Reference Example 5 at a yield of @'kaedoku &-79-.

Example 1 Production of l-O-hequinadecyl-2-o-benzyl-L-threitol (365 drops of metal compound obtained in Reference Example 3)
The mixture was dissolved in 750 ml of 90 ml of tetrachloride, and 2 reduced salt (122,011 J) was added at room temperature, followed by stirring for 5 hours. Ks under reduced pressure
The water was removed by azeotroping with benzene.

Purify the residue using silica gel column chromatography (
Elute with benzene 1:ethyl acetate 1) to obtain the target compound 36.
It was obtained as a white powder of 4 drops (yield: 100 mm).

[α]3-◆&16@CGCL99. methanol).

NMR (ancl, ): a = a88 (l −5H
-J-7Hl).

t27 (#, 24M), 138-t7 (earthquake, 2H)e
'5.5~&54 ('-2H, J-7Hz), 5.5~
&86(g-8H)-455(j, IH, J-12Hz
).

472 ('= 1)1. J-12Hs)-7,52
('-51).

IR(uy):y-3300,2920,2860,1
460tx.

Mhaa:TIl/a=456cM)s 40
5,587゜LO(-!Nin 1: #ethyl acid 1):
Rf=[L7゜夷-Example 2 1-0-hexdecyl-2-o-benzyl-D-! Preparation of lysate aldehyde Add 258 drops (158 mmol) of four vinegar to benzene of SO-, and add 149 M of the chemical compound obtained in Example 1.
Dissolve g (αS9 midamole) in SO- benzene [
The mixture was added dropwise over 1 hour and stirred at 1 temperature for an additional hour. A saturated aqueous sodium sulfate solution was added, filtered and separated, the aqueous layer was further extracted with ethyl acetate, the organic layers were combined, dehydrated and concentrated to give 160 wg of almost pure target compound (yield: 10
Obtained as a slightly yellow oil.

NMR (CD(j,); a-α88(C,5LJfh).

't2y<z,uH>, t3a~t75 (proverb, 2H),
Sensu S (t, 2H, J=7Hz) s 568-480
(IlB-, 211).

584-402 (comic, 1kl), 472 (t, 211)
, 7.52 (#=5ill), 9.66 (j,
IH, J=t21! s).

IR (i [membrane method) Niji-2910, 2850, 1735
, 1440CB-”* Medium Maaa: IN/# ~404 (M), 29
7゜Example 6 Production of 1-0-hequinadefluor 2-0-benzyl-D-dalicerol Compound obtained in Example 2 160 Mg (α4 structure) mixed solvent of methanol and tetrahydrofuran (1:2 V~) 4WJK and stir while stirring at room temperature.
1 Hydride 30aIi (Q, 19 mol) was slowly added and stirred. After cooling, KIN hydrochloric acid was added dropwise, concentrated under reduced pressure, and the residue was purified by gel column chromatography (drained with 9 parts benzene and 1 part ethyl acetate) to give the target compound, 158 Mg (yield). 9816) was obtained as a white powder.

((RiDtomi+tt@(Gα85.methanol).

MMR (CDcjs): ' = 0.88 (' -
5kl, J=7Hz)-127(I, 26H)
, 138-175 (II, 2H).

2.20 (broad' a 1M) -5-45 (' -
2)1. J-711s).

55~Eflo (IK, 5H)-4,58 (a!,
IH, J = 12Hz).

4.75 Cd = IH, J-12i(s), 7.
52 (I-5H) *IR (liquid film method) Niji-3400,
2910, 2840, 1460.

1450m.

Magg:m/g=4g4(M)e 514゜Example 4 Manufacture of 44-isopropylidene-L-threitol 504 da (2 mmol) of ethanol 10ssJK@understood and signed Add Zium-gu 10 [
The water was replaced with bulk gas, and reduction was carried out at -temperature for 1 hour. The catalyst P was separated and concentrated under reduced pressure to obtain a "cra-like compound" compound 2271.
11F86) was obtained as a colorless oil.

NMR ((az,): J=t37(a,3)1)
, 145 (IIJi Ri.

2.96-548 (Broad #, 21(), 544-4
28 (it, 4H).

IR (liquid film method) Niji-3400, 2960, 2910,
2B50°1450.1375.1365m+.

Example 5 (R)-Glycerol acetonite P#) lead astringent tetraacetate t
A mixture of 276 M11 (t7 mmol) of ethyl acetate and benzene<15:85'' obtained in Example 4 was placed in a 72 t (587 ml) 20-inze S moat.
Medium 20-combined? , for 1 hour while stirring at 50C.
7 drops. Further [after stirring at 50C for 1 hour]
Cool to 0CK, filter 1k of impurities, and (R)-! The first batch of lyseraldehyde P acetonide was obtained.

Dissolve sodium borohydride 98011F (2 mmol) in absolute ethanol, stir at room temperature, add dropwise to the previously obtained aldehyde S solution for an hour or so, and stir for another 5 hours. After adding 'Jja' to the grains and stirring for 60 minutes, add 40% of 1N caustic soda.
The mixture was further stirred for 60 minutes, extracted with IIEK ether, and the organic layer was dried and concentrated under reduced pressure. **
Simple vacuum steaming of objects (HP, 110-130G/2mH
)) Kyo') The target compound was obtained as a colorless oil containing 104% F (46%).

1 (α) Dz-119@(Ct72.methanol).

NMR (cDoz, ): J = 139 (1,3M), t
44 (#, 5) 1).

243()0-)”#, 111), A5~45(11
1,5) Ri.

IR (liquid film method): Shiko 5400.2960.2910.
2850°1375, 1565cm-”.

Example 6 Production of 1.2-di-O-indi-5.4-0-inpropylidene-L-threitol
, - dissolve in benzene, and add water to it -
A suspension α4-(approximately 2.21 mol as potassium water) was added at a temperature of K111 while stirring the button. Stir for 30 minutes and press. Next, 248 drops (2.2 tons of damol) of indyl chloride were slowly added. After heating under reflux for 1 hour, cool and add benzene 1
011jtl-added, and ethanol IjIjt was added thereto. Furthermore, I added Benin, washed with water, dehydrated, and then contracted [, 1lIl silica gel column taro! Purified with Todarafi (leaching with benzene/) to obtain target compound 55
6wC yield 92) is a --like substance [lI].

[α]1'--α17@(01t1.Taloronelm).

NMR (GDCj s ) ”-’ 工 t S 5 (
'-3'l)-139 (I-511)-5S6~Eng 6faC11L, 5B), 470~584 (Town 1H).

584-4.04 (expletive, 111), 4.08-436 (
Otori, IM).

4.50 (#, 2H), 4.73 (1, 2) 1),
7.28C1,10M) eIR (liquid film method) Niji = 305
0.3020,2970.2910゜2840.145
5.1380.1345.1080.75&6951
.

Ma5IJ1: vm/a -342 (M”), 32
7-251-TLC (Ethyl acetate 1: Inze 71):R
/=α86°*m Example 7 Production of 1.2-u-0-benzyl-L-slate-λ 2
2M hydrochloric acid 2511J9r was added dropwise while stirring at room temperature, and the mixture was stirred for 1 hour. Concentrate under reduced pressure until it becomes a small amount! The mixture was saturated with sodium chloride and extracted with ethyl acetate. The ethyl acetate layer was washed with water, saturated sodium bicarbonate solution, and water, dehydrated, and concentrated under reduced pressure. Shitsukadal column chromatography with no residue! Purified over 2 days (eluted with ethyl acetate 1:benzene 1) L, 'C targeted metal 42411 (yield 96) Ik was obtained as a colorless ring.

NMil (CDOj, ): J = 129 (#, 2H),
55-4.0 (III.

6M), 4.57 (JF, 2M), 4.62Cz, IH
), 471(#, IH)-7,31('-108)eI
R (liquid film method) Niji = 3370.6050.3020.2
910°28 (50,14?5.1450.109G,
755,695l C air pressure: Il/d=302CM"), 211° DLO (ethyl acetate★1: benzene 1:1): Rf=α27° Example 8 (R)-1,2-diO -Metallic compound 4081% F ('L35t'j
4 L) was dissolved in 20 methanol, and under ice-cooling, 448 molar sodium periodate (2.1 molar) was dissolved in 72 molar water and added dropwise. Stir for another 2 hours while cooling.
-1,2-)-0-penzylchrysealdehyde.

Add Natsukum Polohyde Twide 11411v to this reaction solution.
The mixture was cooled (50 milliliters) and stirred for 1 hour. After removing 20 tm of methanol, the mixture was filtered and PIl was concentrated.

Benzene was added to the residue, water was removed by azeotroping, and the residue was filtered, dehydrated, and concentrated. The chemical compound was obtained as a 643 ml (93 sachets) oil with 1 ethyl acetate;

1 [α], =◆2Q, 0@(0100, methanol).

NMR ((IX3j,): J-41(11, IH), 3
．． 5 to i9 (four groups λ4.57 (a, 2M), 470 (
t, 211), 7.34(a, 1011).

IR (liquid film method) Niji = 5400.3040.3020.
2B60゜1495.1455,1100.740.7
00m-”.

MUe: Town'I=180CM"-92).

Example 9 Production of 1-0-hequinadecyl-2-o-benzi★-D-threitol The desired compound was obtained from the processed food obtained in Reference Example 4 by the method described in Example 1.

True/ [α]D--419° (C1O, methanol).

NMR, IR, and MUe were the same as that of the processed food obtained in Example 1.

Example 1110 Synthesis of 1-0-hequinadecyl-2-o--''-i-dalicerol-enzyme dehyde The compound Ik obtained in Example 8 was oxidized with WSm lead by the method described in Example 2 to obtain the desired The compound was obtained.

NMR, IR, and Mass were all the same as the compound obtained in Example 2.

Example 11 (3) - Manufacture of Daliserolla Dragon Tonaibi A target compound '''C was obtained from the metal compound obtained in Reference Example 4 by the method described in Example 4 and Example 5.

3 crows [α]. =+113' (Ct7.methanol).

Both MMR and IR were the same as the metal compound obtained in Example 5.

Claims (1)

[Claims] 1. General formula (18) or (lA) (la) [lA] (wherein, R1 represents a linear or branched hydrocarbon bulk residue having 8 to 22 carbon atoms or a benzyl group) , R1, R1 is 1m, R
m are both lower alkyl groups, or is R8 a water bulk atom, and IN is a phenyl group or a citalohe1? Is it a tal group or is R8 and R1 a citalohe1? It is shown that the cyclic acetal of the diol can be formed as a cyclic acetal capping group. ). A threitol derivative or D-threitol trout conductor represented by the general formula [厘a] or CIAI (wherein, R1, R'', and Rm have the same meaning as described in claim 1) 1,2-Diol of the compound represented by )
A D- or L-glyceraldehyde derivative represented by
, R2, and R1 have the same meaning as the key notation. ) A method for producing a D- or L-glycerin derivative characterized by the following characteristics: